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JOURNAL of SCIENCE & RESEARCH
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Volume:01 2016
Herbal Remedies for Dengue Fever 01
Dr. Shahid Rasool

Sustained Release Bilayer Tablet 09
Mr. Sahilhusen I. Jethara1, Dr. Mukesh R. Patel

Design and Development of Reconstitutable Sustained Release 37
Suspension of Linezolid by Spray Drying Technique
Sahilhusen I. Jethara, Mukesh S. Patel, Mukesh R. Patel , Mahesh J. Pagi

Journal of Science & Research Pakistan.
Published by:Science Organization Pakistan
27 –Ramzan-ul-Mubarak 1437/ 03 july 2016
Dr. Shahid Rasool
Assistant Professor
Faculty of Pharmacy
University of Sargodha
Herbal Remedies for Dengue Fever
Dengue is an acute mosquito-transmitted viral disease (Jose et al., 1998). Now a days dengue is a prevalent mosquito-borne infection in human beings, which has become major international public health issue. Symptomatically dengue virus infections can present with a spacious range of clinical signs, from a mild feverish illness to a life- threatening shock syndrome. Both viral and host factors are thought to contribute to the appearance of disease in each infected person (Jahan 2011). Dengue viruses occur as four antigenically related but discrete serotypes transmitted to humans by Aedes aegypti mosquitoes 1988). Southeast Asia, western Pacific, and the America are endemic regions where incidence and case fatality is observed for dengue and Dengue Hemorrhagic Fever (DHF). For diagnosis of the disease, different methods for viral isolation and the serological, immune histo-chemical, and molecular methods are also reviewed (Maria 2002). This severe syndrome recently has also been recognized in children infected with the virus in Puerto Rico that is characterized by increased vascular permeability and abnormal homeostasis. Replication of dengue viruses takes place in cells of mononuclear phagocyte lineage, and enhances dengue virus infection by sub neutralizing the concentrations of dengue antibody. This antibody-dependent enhancement of infection regulates dengue disease in human beings. Disease can also be controlled genetically, possibly by allowing and restricting the growth of virus in monocyte1988). Efforts to control this disease are dependent on understanding the pathogenicity of dengue viruses and their transmission dynamics. Pathogenicity study is in a weak position by the lack of in vitro or in vivo models of austere dengue disease (Rebeca et al., 1997). The status for vaccine development is described and emphasize that the only alternative that we have today to control the disease is through control of its vector Aedes aegypti (Maria ANTIVIRALS
Kaempferia parviflora
Local name of Kaempferia parviflora is chandramul. Chemical constituent is borneol. It belongs to Zingiberaceae family. Leaves and stem are used as herbal remedy against virus. Four serotypes for Dengue have been recognized i.e. DEN 1(Dengue 1), DEN 2, DEN 3, and DEN 4. Recent studies show that DEN 2 particles are directly inactivated by some bioactive compound in K. parviflora. The plant extract activity is dose dependent (Hafidh et al., 2009). Figure 1: Borneol Quercus lusitanica
Loacal name of Quercus lusitanica is mazu phal. Chemical constituent is gallic acid and ellagic acid. Its whole plant is used as drug. Quercus lusitanica, also known as Quercus infectoria, is a small tree or a shrub belonging to the Fagaceae (Quercaceae) family. Test was performed on methanol crude and fractionated extracts of Quercus lusitanica. The cytotoxicity of these plant extracts was evaluated by determining the maximum non-toxic dose (MNTD) on C6/36 cells. Antiviral activity was estimated by the reduction of the cytopathic effect (CPE) of DENV-2 in C6/36 cells and by the reduction of virus titre. The crude methanol extracts of Q. lusitanica at the concentration of 180μg/ml was found to completely inhibit the dengue virus infection. The extract of the plant inhibits the replication of virus (Noorsaadah et al., 2006). a) Figure 2: a) gallic acid, b)ellagic acid LARVICIDALS
Piper longum
Local name of Piper longum is pipal, pippli. It belongs to family Piperaceae. Three species i.e. Piper longum L., P. ribesoides Wall and P. sarmentosum Roxb of this family have been used (as ethanolic extract) in research. Efficacy of these species is in following order: P. longum > P. sarmentosum Roxb > P ribesoides Wall. This study conclude that Pepper plant possess activity against Aedes aegypti (Chaithong et al., Murraya koenigii
Local name of Murraya koenigii is Kari patah or Kariapat. Family is Rutaceae. It is aromatic deciduous shrub of small tree. Whole plant is used as herbal remedy. The hexane, diethyl ether, dichloromethane and ethyl acetate crude extracts of the whole plant was prepared and pupa and adult mosquitoes were allowed to grow over there. During the experiment larvae and adults were fed normally. As a result of the experiment, larval and pupal deformations were observed and there was also inhibition of adult emergence. Hence, it causes abnormalities in adult formation. So, it can be used as larvicidal (Arivoli and Samuel 2011). Pimpinella anisum
Local name of Pimpinella anisum is Anisuan. It belongs to the family Apiaceae. Whole plant is used to extract essential oil which is composed of linalool, methylchavicol, α-terpineol, cis-anethole, trans-anethole and p-anisaldehyde. Trans- anethole has mutagenic activity. The essential oil of this plant is highly toxic to larvae of Aedes aegypti (Veena et al., 2005). Figure 3: Trans-anethole Curcuma longa
It is rhizomatous, herbaceous perennial plant of ginger family, Zingiberaceae. Its rhizome is used as herbal remedy. It is also used in foods and in cosmetics. Ethyl acetate extract from Curcuma longa rhizomes give three curcuminoids which show activity in inhibiting topoisomerase I and topoiso merase II. Out of these three curcuminoides, curcumin III is the most effective. Turmerone obtained from volatile oil of Curcuma longa gives 100% mosquitocidal activity against Aedes aegypti (Roth et al., 1998). Figure 4: a) Curcumin III, b) α- Turmerone, c) β- Turmerone Murraya koenigii
The hexane, diethyl ether, dichloromethane and ethyl acetate crude extracts of the whole plant was prepared and adult mosquitoes were allowed to grow over there. During the experiment adults were fed normally. As a result of the experiment there was the inhibition of adult emergence by losing their consciousness. Hence, adults cannot bite and don't show any activity because of the knock-down ability of this plant. Thus, it can be used as Mosquitocidal (Arivoli and Samuel, 2011). MOSQUITO REPELLENTS
Eravatamia coronaria
It belongs to the family Apocynaceae. Its leaves are used as herbal remedy. Crude benzene and ethyl acetate extracts of the leaves of Eravatamia coronaria are used as repellent for Aedes aegypti. The results are collected by studying the repellent activity at three different concentrations 1.0, 2.5, and 5.0 mg/cm. These concentrations were applied on the skin of forearm of a man and exposed against female Aedes aegypti. This plant gives protection against this mosquito without any allergic effect and this activity is also dependent upon the dose concentration et al., 2009). Caesalpinia pulcherrima
It belongs to the family Fabaceae. Part used is leaf. Crude benzene and ethyl acetate extracts of the leaves of Caesalpinia pulcherrima are used as repellent for Aedes aegypti. The results are collected by studying the repellent activity at three different concentrations 1.0, 2.5, and 5.0 mg/cm. These concentrations were applied on the skin of forearm of a man and exposed against female Aedes aegypti. This plant gives protection against this mosquito without any allergic effect et al., Andropogon citratum
It belongs to the family Poaceae. Its common name is citronella grass. Active constituent of this plant is essential oil, citronella oil. This oil is put in candles and lanterns that can be burned to repel mosquitoes. Its mosquito repellent qualities have been verified by research, including effectiveness in repelling Aedes aegypti (Onanong et al., 2009). Figure 5: Citronella oil composed of a) Citronellal, b) (+)-Citronellol , c) (-)- Citronellol, and d) Geraniol The nanoemulsions of this plant oil were made and was investigated both in-vivo and in-vitro. High pressure homogenization to convert larger emulsion droplets (195-220 nm) to smaller size droplets (150-160 nm) results in higher release rate. Thin films are obtained from nanoemulsions which have droplets of small size. Such films have more integrity, hence, they increase the vaporization of essential oils subsequently prolong the activity of mosquito repellent (Ibrahim et al., 1998). Syzygium aromaticum
Its family is Myrtaceae. Its Urdu name is Laung. Essential oil of this plant is used as insect repellents. Experiments show that undiluted clove oil can repel many species of mosquitoes for up to two hours. However, this concentrated clove oil may cause skin rash in sensitive people. Recommended dilution is less than 24% (Dan et al., 2004). CONCLUSION
Natural drugs possess activity against Aedes aegypti by their antiviral mechanism, larvicidal and mosquitocidal action and mosquito repellents property. Work on structural activity relationship of active compounds found in studied plants may help to develop new medicines for the prevention and treatment of dengue. REFERENCES
Arivoli and Samuel Tennyson. (2011). Studies on the mosquitocidal activity of murraya koenigii (L.) Spreng (Rutaceae) leaf extracts against Aedes Aegypti Anopheles stephensi and Culex quinquefasciatus S. Asian journal of Experimental Bioogical Sciences. 2(4), 721-730. Chaithong,U., Choochote, W., Kamsuk,K., Jitpakdi,A., Tippawangkosol, P.,Chaiyasit, D., Champakaew, D., Tuetun, B. and Pitasawat, B., (2006) Larvicidal effect of pepper plants on Aedes aegypti. Journal of Vector Ecology. 31(1), 138-144. Dan, B., Steven, C., Erich, S. and Andrew G. (2004). Chinese Herbal Medicine: Materia Medica (3rd ed.), Eastland Press, pp. 1311. M., TK., KA.(2009) Parasitology Research. 109 (2), 353-67. Hafidh, R.R., Abdulamir, A.S., Jahanshiri, F., Abas, F., Abu Bakar, Sekawi, Z. (2009) Asia is the Mine of Natural Antivira l Products for Public Health. The Open Complementary Medicine Journal.1, 58-68. S.B. (1988) Pathogenesis of dengue: J. Challenges to Molecular Biology Ibrahim, J. and Zaridah, Z., (1998) Development of environment- friendly insect Repellents from the Leaf oils of selected malaysian plants. ASEAN Review of Biodiversity and Environmental Conservation (ARBEC). Article VI, Page 1. Jahan, F. (2011) Dengue Fever (DF) in Pakistan. Asia Pacific Family Medicine. 10(1). José,G., Rigau, G., Duane, J.,Gubler, S.D., Paul R.D., Eduard, J.,Sanders, M.D. (1998) Dengue and dengue haemorrhagic fever. The Lancet. 352(9132), 971-977. Maria, G. and Gustavo,K. (2002). The Lancet Infectious Diseases. 02(1), 33-42.
Noorsaadah, R., Hadinur, Sylvia Muliawan, Nurshamimi or Rashid, Mudiana Muhamad and Rohana, Y. (2006) Studies on Quercus lusitanica Extracts on DENV-2 Replication. Drug Bulletin.30(1). Onanong, N., Usawadee S., Napaporn, U., Satit, P., Apinan S.and Uracha, R. (2009) In vitro characterization and mosquito (Aedes aegypti) repellent activity of essential- oils- loaded nanoemulsions. Aaps Pharmscitech. 10(4), 1234-1242. Rebeca R.H., Lisa, M.H., Rosa A.S., Duilia, T., Ananda,N., Celso R., Jorge, B., Maria T. R., Rita M.R. (1997) Origins of Dengue Type 2 Viruses Associated with increased Pathogenicity in the Americas. Virology, 244-251. Roth, G.N., Chandra, A., Nair, M.G. (1998) Novel bioactivities of Curcuma longa constituents. Journal of Natural Products. 61(4), 542-5. Veena, P., Tripathi, A.K., Aggarwal, K.K., Khanuja, S.P.S. (2005) Insecticidal, repellent and oviposition-deterrent activity of selected essential oils against Anopheles stephensi, Aedes aegypti and Culex quinquefasciatus. Bioresource Technology, 96(16), 1749-1757. Journal of Science & Research Pakistan.
Published by:Science Organization Pakistan
27 –Ramzan-ul-Mubarak 1437/ 03 july 2016
Novel Sustained Release Bilayer Tablet Technology
Running Title: Sustained Release Bilayer Tablet
Mr. Sahilhusen I. Jethara1, 2*, Dr. Mukesh R. Patel 2
1 Research scholar, Gujarat Technological University, Gujarat, India 2Shri B. M. Shah College of Pharmaceutical Education & Research, Modasa-383315, Gujarat, India. *Correspondence Author
Mr. Sahilhusen I. Jethara,
Department of Pharmaceutics, Shri B. M. Shah College of Pharmaceutical Education and Research, Modasa -383315, Gujarat, India Mobile : +918460378336 ABSTRACT
Combination therapy is novel technique for the treatment of the disease. Sustained release technology is relatively contemporary field and combination of two drugs which have different release profile is also new concept of dosage form. Bilayer tablets are favored in some cases because they maintain uniform drug levels, reduce dose, side effects, increase the safety margin for high-potency drugs and thus offer better patient compliance. Curative strategies based on oral delivery of bilayer tablets are gaining more acceptances along with brand and generic products due to a convergence of factors including advanced delivery strategies, patient compliance and combination therapy. Successful manufacturing of these ever more complex systems needs to overcome a series of challenges from formulation design to tablet press monitoring and control. This article provides an overview of the state-of-the-art of bilayer tablet technology, highlighting the main benefits of this type of oral drug delivery while providing an elucidation of current challenges and advances toward improving manufacturing practices and product quality. The accessible features of the manufacturing equipment for bilayer tablet production are also described indicating the different strategies for sensing and controls offered by bilayer tablet press manufacturers. This patent reviews covers different pharmaceutical bilayer tablets, technologies, challenges and applications in bilayer drug delivery as well as the recent marketed published or granted patent surveys. A better understanding of these patents, novel researches and patented technologies will help researchers and pharmaceutical industries to select the appropriate platform, or to develop innovative products with improved bilayer tablets properties. Keywords : Bilayer Tablets, Sustained Release, Patient compliance, Tabletting technology
Combination therapy is new technique for the treatment of the disease. Sustained release technology is relatively modern field and combination of two drugs which have different release profile is also new concept of dosage form. With many drugs, the basic purpose is to achieve a steady state blood level. The success of a therapy depends on selection of the appropriate delivery system as much as drug itself. Bi- layer tablets are prepared with one layer of drug for immediate release or sustained release while second layer designed to release drug, later, either as second dose or in an extended release manner. Bi- layer tablet is suitable for sequential release of two drugs in combination, separate two incompatible substances, and also for sustained release tablet in which one layer is immediate release as initial dose and second layer is maintenance dose [1, 2]. The main challenges of combining two or more drug in the same pharmaceutical form are (i) to ensure the physiochemical compatibility between the different active ingredients and/or between the active ingredients and the excipients used; and (ii) to ensure the therapeutically compatibility between the two active ingredients regarding their pharmacokinetic and/or pharmaceutical properties in order that the posology of the combined composition allows to obtain safe and efficient plasma level of both pharmacological agents. Different approaches have been proposed to formulate sustained release tablets for retaining dosage form in stomach. These include bioadhesive or mucoadhesive systems, swelling and expanding systems, floating systems and other delayed gastric emptying devices [3, 4]. Fig. (1). Bilayer tablet represents; (a) phase I comprising a sustained release layer and (b) phase
II comprising a sustained release or immediate release layer. It is desirable to provide oral pharmaceutical formulations which release their active material content at a controlled rate after oral administration, so that for example release of the active material into the stomach or intestine occurs over a period of several hours after ingestion of the formulation. The differing relative rate of release of active material content from the first and second layers of the tablet may be achieved in various ways. For example differing rates of release may be achieved by a first layer which is a rapid release layer, i.e. which releases the bulk of its active material content within a relatively short time, for example within 1 hour, e.g. within 30 minutes after oral injections, and a second layer which is a slow release layer, i.e. which releases the bulk of its active material content during a relatively long period after oral ingestion or is a delayed release layer which releases the bulk of its active material content after a period of delay after oral ingestion, either in the stomach or in the intestine [5]. Fig. (2). Steps involved in preparation of bilayer tablets.
a) First layer fill b) First layer tamping c) Upper punch withdrawal d) Second layer fill e) Main compression Rapid release layers may for example be rapid disintegrating layers having a composition similar to that of known rapid-disintegrating tablets. An alternative type of rapid-release layer may be a swellable layer having a composition which incorporates polymeric materials which swell rapidly and extensively in contact with water or aqueous media, to form a water permeable but relatively large swollen mass. Active material content may be rapidly leached out of this mass. Slow release layers may have a composition which comprises active material content together with a release retarding material. Release-retarding polymers which have a high degree of swelling in contact with water or aqueous media such as the stomach contents, polymeric materials which form a gel on contact with water or aqueous media, and polymeric materials which have both swelling and gelling characteristics in contact with water or aqueous media [7]. Polymers which have a high degree of swelling include, inter alia, cross-linked sodium CMC, cross- linked HPC, high- molecular weight HPMC, carboxymethylamide, potassium methacrylate divinylbenzene co-polymer, polymethylmethacrylate, cross- linked PVP, high molecular weight PVA etc. Gellable polymers include MC, CMC, low-molecular weight HPMC, low- molecular weight PVA, polyoxyethyleneglycols, non-cross linked PVP etc. Polymers simultaneously possessing swelling and gelling properties include medium- viscosity HPMC and medium- viscosity PVA. Such a slow release layer may contain polymers which rapidly swell in contact with water or aqueous media so that they form a relatively large swollen mass which is not rapidly discharged from the stomach into the intestine. Suitably such a slow release layer may contain around 30-70% e.g. 40 - 60%, of active material content, around 15-45% of release- retarding polymers, around 0-30% of fillers/compression aids, conventional quantities of disintegrants and lubricants, and some 5 - 20% of soluble excipients [8, 9]. Delayed-release layers may use the known properties of enteric polymers to delay release of active material content until the whole or part of the tablet is discharged by the stomach into the intestine after oral ingestion. Enteric polymers are insoluble or only slightly soluble in the stomach contents, but relatively soluble in the higher pH intestinal environment. Individual particles, e.g. granules of active material content may be coated with a layer of or made up with an enteric polymer, and embedded or dispersed within a soluble or disintegrable matrix. Differing rates of release may also be achieved by having a first layer which is a slow or delayed release layer, and a second layer which is also a slow or delayed release layer. Such first and second layers may for example differ in their composition, so that they comprise different quantities, combinations or types of release-retarding materials and/or soluble excipients etc. Additionally or alternatively such first and second layers may for example differ in the relative amounts of active material content in the first and second layers [10, 11]. ADVANTAGES OF BILAYER TABLETS
Several advantages of the bilayer technology were reported in the literature. The main ones are  Two chemically incompatible drugs can be formulated in a bilayer design. In some cases, depending on the amount of the incompatibility between the two drugs, an in-between layer needs to be added to provide physical separation between the two layers [12, 13].  Two APIs or the same API with different release profiles can be delivered as a single bilayer tablet (e.g. drugs with an extended release and an immediate release profiles) [14].  Combining two or more APIs in a single bilayer tablet reduces the dosing unit burden thereby improving patient compliance [15, 16].  As most bilayer tablets are developed as part of a Life Cycle Management program, the bilayer technology provides possibility of prolonging patent life of a drug product [17].  Increased efficacy of the active components due to their synergistic effect [18, 19]. KEY CHALLENGES OF BILAYER TABLETS
The researchers and development scientists need to conquer the challenges to deliver a bilayer tablet and manufacturing process. Some of the key challenges are [20]:  Layer separation.  Insufficient bilayer tablet hardness.  Inaccurate individual layer weight control.  Cross contamination between the layers.  Reduced yield.  Long term physical and chemical integrity throughout shelf life.  Large tablet size, which can impact the swallowability of the unit dose.  Impact of high temperature and humidity on layer adhesion upon storage. Overcoming all these challenges requires a focused effort toward addressing the following areas related to material properties and bilayer processing parameters:  Determination of mechanical properties of each layer.  Maximization of interfacial adhesion between the layers.  Optimization of the first layer compression force.  Quantification/understanding of factors contributing to delamination.  Assessment of the impact of layer sequence and layer weight ratio.  Development of techniques for small scale material characterization tools that can be applied during bilayer tablet design.  Selection of appropriate bilayer tablet press alternatives with consistent weight control delivering system. Fig. (3). Problems with the bilayer tablet; (a) capping, (b) lamination and (c) possible cause of
capping/lamination. NOVEL TECHNOLOGIES FOR BILAYER TABLET
For managing bilayer tablet technologies are being categorized as: 1. OROS® push pulls Technology
 Bi-layer and tri-layer OROS Push pull technology 2. L-OROSTM Technology
3. EN SO TROL Technology
4. Geminex technology
5. DUREDAS™ technology
6. Dual release drug absorption system
Bi- layered tablets to ensure two release rates for the dosage form. 7. Programmable oral drug absorption system or PRODAS
Multi-particulate drug delivery technology that is based on the encapsulation of oral controlled release mini tablets in the size range of 1.5 to 4 mm in diameter. 8. Multi-porous oral drug absorption system
It consists of core surrounded by time release coating, which on interacting with gastric fluid transforms to a semi-permeable membrane which regulates drug release. 9. DUROS technologies
Implants with tiny titanium cylinders designed to provide continuous osmotically ambitious delivery of drugs within the body. 10. VERSATAB Controlled
Controlled-release tablets are oral dosage forms from which the active is released over an extended period of time (up to 24 hours) upon ingestion. 11. Geomatrix technologies
Multilayer tablet designed specially to regulate amount location and time of drug release. 12. Rotab Bilayer
13. TIMERx technologies
Matrix tablet composed of locust bean X gum and xanthan gum. 14. Osmotic tablet system single composition (SCOT)
Use osmotic principle to achieve zero order drug release [21, 22]. PROGRESSION OF THE RESEARCH TOPICS AS EXAMINED BY TOP CITED
Some of these articles are very informative and disclose background on the formulation and review of bilayer tablets as summarized in Table 1. As the topics in Table 1 indicate, novel
research in drug delivery have advanced from understanding the drug release mechanisms and disclose background on the different drug formulations and review of bilayer sustained release tablet as review in Table 1. Table 1: Leading novel researches on bilayer tablet formulations
Delivery
Description
Metoclopramide HCl Bilayer tablets Avoid chemical incompatibility between [23] drugs and effective treatment of migraine. + Bilayer tablets To overcome bioavailability and patient [24] compliance problem, and reduces dosing Bilayer matrix To avoid interaction between incompatible [25] Diclofenac sodium + Bilayer tablets Synergistic effect in gout. Avoid incompatibility between drugs and to [27] improve the stability of drugs in combination Aspirin + Clopidogrel To enhance bioavailability and synergistic [28] effect in acute coronary syndromes. Metoprolol Tartarate + Bilayer tablets Reduces the frequency of dosing, reduce pill [29] burden and thus improve the patient Bilayer matrix Bimodal release system to manage pain Metoprolol succinate Bilayer matrix To control excess blood pressure in the [31] management of severe cardiovascular events especially essential hypertension by once compliance and therapeutic efficacy. + Bilayer tablets Improved patience compliance and better [32] Sitagliptin Phosphate disease management Bilayer buccal To reducing side effects Bilayer tablets Synergistic effect in diabetes Bilayer tablets To develop polytherapy for the treatment of Type II diabetes and hyperlipidemia Bilayer tablets Biphasic release profile Bilayer tablets Synergistic effect of drugs in pain Amlodipine Besilate + Bilayer tablets Synergistic effect in hypertension Metoprolol Succinate Bilayer tablets Synergistic effect of drugs in back pain Biphasic drug release Bilayer tablets Decrease frequency of administration and [41] improve patient compliance Bilayer tablets Prolonged release up to 12 h and improve [42] patient compliance Bilayer tablets Improve patient compliance and prolong [43] Atorvastatin calcium+ Bilayer tablets Develop potential dosage form Bilayer tablets To minimize contact b/w drugs Diclofenac sodium Bilayer tablets Bimodal drug release To minimize contact b/w drugs Bilayer tablets To improve the stability of drugs in [48] Bilayer tablets To improve the stability of drugs in [49] Bilayer tablets Synergistic effect in pain Cyclobenzaprine HCl Bilayer buccal To reducing side effects and frequency of Cefixime Trihydrate + Bilayer tablets Synergistic effect in bacterial infections Dicloxacilline Sodium TYPES OF BILAYER TABLET PRESSES
1. Single sided tablet press
The simplest design is a single-sided press with both chambers of the double feeder separated from each other. Each chamber is gravity- or forced-fed with a different powder, thus producing the two individual layers of the tablet. 2. Double sided tablet press
A double-sided press offers an individual fill station, pre-compression and main compression for each layer. Most double-sided tablet presses with automated production control use compression force to monitor and control tablet weight. 3. Bilayer tablet press with displacement monitoring
The displacement tablet weight control principle is fundamentally different from the principle based upon compression force. When measuring displacement, the control system sensitivity does not depend on the tablet weight but depends on the applied pre compression force. 4. Piccola bilayer
This rotary press was designed to represent two-layer tablet production conditions at a small scale, according to the needs of new product development [53, 54]. BILAYER TABLET DEVELOPMENT
The review thorough in this article related to various material properties, characterization tools and bilayer compression process in view of guiding the formulation and process scientists to develop a bilayer product is summarized in the following schematic presentation (Figure 4) [55, Characterize the layers individually;
Selecting the first layer material based on;
Compaction characteristics (compatible and compressible material is preffered) Surface morphology (brittle materials are preferred) Good flow property The material selection for first layer sometimes governed by layer weight ration and bilayer press limitations.
Small scale Characterization of the first layer material solely in terms of;
Hardness/compression force profile Pre-and main-compression consolidation characteristics.
Elastic properties Maximize interfacial adhesion between the layers Particle size distribution (relatively lower levels of fine particles in order to minimize cross Small scale characterization of the second layer (same as above).
Select appropriate bilayer press
Determination of the pre-compression force for the first layer
1st and 2nd layer weight ratio (this is critical due to compaction press limitations- punch
penetration)

Generally, 1st layer with higher weight and 2nd layer with lower weight recommended.
Bilayer tablet, which comply with the requisite quality attributes
Fig. (4). Characterization and manufacturing process of bilayer tablet.
PATENTS ON BILAYER TABLETS
Summary of bilayer tablets based patents for sustained release drug delivery system given Table 2 [57-109].
Table 2. List of Various Patents on Bilayer Tablets
Patent No.
Description
Misoprostol sustained release, bilayer buoyant dosage US5232704 (1993)
The present invention relates to a method of treating AU724576 (1998)
hypertension and heart failure with the co-administration [58] of Enalapril and Losartan. The invention relates to novel tablet formulations for oral EP1025841 B1 (2000)
administration of Amoxycillin optionally together with Clavulanic acid. US2003/0092724 A1 Oxycodone or Hydrocodone or Oxymorphone and WO2003/059327 A1 Hydochlorthiazide. US2003/0203021 A1 Phamaceutical composition containing Epinastine and [62] Pseudoephedrine. US2004/0241227 A1, Bacterial infection may be treated using regimen of amoxicillin and potassium clavunate. Preferably, the dosage is provided by a bilayer tablet. US2004/0180089 A1 Simatriptan succinate. EP1404304 B1 (2004)
Bilayer tablet comprising Cetirizine and Pseudoephedrine. US20040253311 (2004)
Ibuprofen and Loratadine (first layer) and Phenylephrine (second layer). Investigation has found that the use of HPMC in magnesium oxide allows significant additions controlled of the release profile of a compacted tablet. US20040115265 (2004)
Aspirin and Pravastatin bilayer tablet, and prevents or minimize interaction of aspirin with pravastatin. US20040097536 (2004)
Pseudoephedrine sulfate. A dual- layer release-controllable osmotic breviscapine tablet for treating cerebral thrombosis, coronary heart disease and cardiovascular disease. CN1615123 A (2005)
Bilayer pharmaceutical tablets comprising telmisartan and hydrochlorothiazide EP1569651 B1 (2005)
A bilayer tablet composition for the delivery of Efletirizine [72] HCl Pseudoephedrine HCl. US20050089575 (2005)
Hydochlorthiazide. The bilayer tablet structure overcomes the stability problem caused by the incompatibility of Hydochlorthiazide. Angiotensin II receptor antagonist Telmisartan and HMG- WO2006/040085 A3, CoA reductase inhibitor Simvastatin. WO2006/0078615 A1 US20060057202 (2006)
Bilayer tablet of Thiazolidinediones and Biguanide with once a day dosing. WO2009/024949 A2 Ziprasidone HCl controlled release dosage form combining immediate release and sustained release of low solubility US2006/0110450 A1 Bilayer tablet of Telmisartan and Amlodipine US2006/0141037 A1 Bilayer tablet of Oxcarbazepine, which maintain a Oxcarbazepine with once a day administration. US2008/0095846 A1 Bilayer tablet containing Fexofenadine HCl anhydrous Pseudoephedrine HCl. EP1992333 A1 (2008)
Bilayer tablet of Flurbiprofen and muscle relaxant (e.g. [82] Tizanidine HCI and Thiocolchicoside) combinations. WO 2009/118764 Al Bilayer tablet of diclofenac sodium and paracetamol. WO2009/049405 Al A bilayer composition for the delivery of Acetaminophen and Tramadol over at least a 12 hour period following initial administration. WO2009/016577 A2 A bilayer tablet comprising Atorvastatin and Niacin. US2009/0269393 A1 Chewable Cetirizine bilayer tablet US2009/0130183 A1 Bilayer tablet composition for the sustained release of acetaminophen and tramadol. US2010/0172984 A1 Tablet dosage form comprising Cetirizine HCl and Pseudoephedrine HCl. US2010/0178341 A1 A bilayer tablet comprising Niacin and Simvastatin. WO2010/091197 A1 Tablets for combination therapy CN101732274 A (2010)
A colchicine bilayer sustained-release tablet which [91] comprises a quick release layer and a sustained-release CN101623270 A (2010)
Stable artesunate and amodiaquine hydrochloride bilayer CN102008472 A (2011)
A compound preparation of pioglitazone HCl and metformin HCl bilayer osmotic pump controlled release CN102085196 A (2011)
The nefopam hydrochloride bilayer sustained-release tablet CN102085201 A (2011)
Atenolol and amlodipine bilayer tablet WO2012/172413 A1 Bilayer tablet of Epirisone HCl and Diclofenac sodium. US2012/0282336 A1 Bilayer tablet containing Metformin and Dapagliflozin US2013/0330406 A1 EP1814527 B1 (2013)
A bilayer tablet comprising angiotensin II receptor [100] antagonist Telmisartan and calcium channel blocker WO2013/001541 A1 An optimized bilayered tablet dosage form with high rate [101] of bioavailability of two active antibiotics such as Cefuroxime and Clavulanic acid. WO2013/001543 A1 An optimized bilayered tablet dosage form with two active antibiotics such as Clavulanic acid and Cefpodoxime WO2013/115736 A2 WO2013/124768 A1 A bilayer tablet composition of Dronedarone which [104] maintains a therapeutically effective blood concentration with once a day administration. Omeprazole enteric bilayer slow-release tablet. WO2013/035188 A1 Bilayered composite tablet formulation comprising [106] Atorvastatin, Irbesartan and Magnesium carbonate. US2014/0037725 A1 Bilayer tablets of Naproxen sodium US2014/0255484 A1 Modified release bilayer tablet composition of [108] US8785432 B2 (2014)
A bilayer tablet dosage form comprising Amlodipine [109] besylate and Valsatan. EVALUATION PARAMETERES OF SUSTAIN RELEASE BILAYER TABLET
The characterization of the bilayer is also similar to that of the simple conventional tablet such as color, size, shape, density and other important characteristics as mentioned below. a) Pre-compression parameters
 Particle size distribution  Photon microscope study  Angle of repose  Moisture sorption capacity  Density o Bulk density (BD) o Tapped density (TD)  Carr's index  Hausner Ratio b) Post-compression parameters
 Thickness and diameter  Size and shape  Hardness  Friability  Uniformity of weight  Dissolution studies  Disintegration test  Drug content  Wetting time and water absorption ratio  Stability study as per ICH guidelines CONCLUSIONS
This patent review article provides an updated bird's eye view survey account on the publications and patents of different novel delivery approaches for use in oral applications. Owing to its tremendous attributes, oral controlled delivery exploitation has amazed the researchers involved in accomplishing an efficient therapeutic delivery via bilayer tablets. Even though oral delivery meets the need for self-administered drugs but targeted, sustained release, patient compliance and increased bioavailability present the areas of difficulty in meeting the emerging value proposition. Bilayer tablets by design are heterogeneous systems composed of two (or more for multi- layers) different layers separated by a discrete interface. This heterogeneity is the main source for the additional challenges in the design and manufacture of bilayer tablets. The properties of compacted products such as hardness and lamination tendency depend not only on the formulation but also on the deformation history of each layer during tablet manufacturing. While for bilayer tablets the impact of deformation history is reasonably well characterized and understood, for bilayer tablets it requires further studies due to the interdependency between first and second layer interactions, including thickness, weight and force. Variations in one single parameter result in changes in the properties of both layers and also the interface. In this article, some key issues were identified for bilayer tablet manufacturing attendant to the need for understanding heterogeneous systems while providing an overview of prior and current strategies to address them. In this review, the patents have been reviewed to show the assortment of the bilayer tablets. These systems hold a major market share in the drug delivery products as exemplified by the number of products in the market and patents granted in the last few years. Therefore, the present review described about achievements of bilayer tablets in oral drug delivery system in order to improve the patient compliance, they maintain uniform drug levels, reduce dose, side effects and increase the safety margin for high-potency drugs. In future more research work can be carried out for further developments in oral bilayer drug delivery systems. US = United States Patent CN = China Patent WO = World Intellectual Property Organization (WIPO) EP = European Patent CA = Canadian Patent AU = Australian Patent HPMC = Hydroxy Propyl Methyl Cellulose EC = Ethyl Cellulose Sodium CMC = Sodium Carboxy Methyl Cellulose MC = Methyl Cellulose CMC = Carboxy Methyl Cellulose PVA = Polyvinylalcohols HPC = Hydroxypropylcellulose PVP = Polyvinylpyrrolidone CONFLICT OF INTEREST
The author declares no conflict of interest. The author would like to thank Dr. M. R. Patel for his comments on this article. REFERENCES
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Journal of Science & Research Pakistan.
Published by:Science Organization Pakistan
27 –Ramzan-ul-Mubarak 1437/ 03 july 2016
Design and Developme nt of Reconstitutable Sustained Release
Suspension of Linezolid by Spray Drying Technique
Running Title: Novel Oral Reconstitutable Sustained Release Suspension
Sahilhusen I. Jethara1, 2*, Mukesh S. Patel2, Mukesh R. Patel2, Mahesh J. Pagi2
1 Research scholar, Gujarat Technological University, Gujarat, India
2Shri B. M. Shah College of Pharmaceutical Education & Research, Modasa-383315,
Gujarat, India.
*Correspondence Author
Mr. Sahilhusen I. Jethara,
Department of Pharmaceutics, Shri B. M. Shah College of Pharmaceutical Education and Research, College Campus, Modasa -383315, Gujarat, India Mobile : +918460378336 ABSTRACT
The purpose of this research work was to design and evaluation of a stable reconstitutable Sustained release suspension for pediatric and geriatric patients using spray drying techniques. Linezolid is the drug of choice in treatment of infections caused by multi-resistant bacteria. The microcapsules were prepared by spray drying method. Drug loaded microcapsule were prepared using Eudragit RS and RL100 and ethyl cellulose in three different polymer ratio. The influence of the drug to polymer ratio and feed flow rate was studied on the properties of microcapsule using a 32 factorial design. The drug to polymer ratio (X1) and feed flow rate (X2) were selected as independent variable and percentage yield, particle size, encapsulation efficiency, Q6, Q8, t90% were selected as dependent variables. Regression analysis and ANOVA were performed for dependent variables. Dissolution data were fitted to various kinetic models on drug release of microcapsule. The prepared SR suspensions were evaluated for flow properties, determinat ion of rheological and sedimentation behavior. From the factorial batches, optimize batch of microcapsules were used for preparation of reconstitutable SR suspension using various suitable suspending agents. Accelerator stability study of reconstitutable SR suspension was performed as per ICH guideline. From the study of the preliminary and factorial batches, all the physical characteristics of microcapsules are in acceptable range. Results was clearly indicated that drug to polymer ratio and feed flow rate had significant influence on percentage yield, particle size, encapsulation efficiency, Q6, Q8, t90, Diffusion coefficient (n) and Release rate constant (k). Form the study, the optimized formulation (S3) showed 99.12% drug release at the end of 12 hrs with drug to polymer ratio (1:1.3) and feed flow rate (5 ml/min) respectively for obtaining the higher percentage of yield, maximum encapsulation efficiency, Particle size of microcapsules which is found to be 87.82%, 99.07% and 16.06 µm consequently. SEM showed that microcapsules were spherical with smooth surface. The dissolution profile of optimize batch exhibits similarity factor (f2=82.35) and dissimilarity factor (f1=2.90) with theoretical release profile of linezolid. Microcapsule prepared with 1:1.3 drug to polymer ratio were selected for SR suspension formulations since they have higher loading efficiency and suitable micromeritic properties to disperse in aqueous medium. Results reported the release profiles of suspension prepared from microcapsules had no significant difference (P>0.05) was observed in CPR for sustained release suspension on 1day and after 15days which indicates the suspension stability. Results clearly revealed that drug release studies of SR suspension formulation did not show any statistically significant differences (P>0.05) from the properties of microcapsule alone. Keywords : Microencapsulation, Spray drying, Reconstitutable sustained release suspension,
The basic goal of any treatment is to cure the sign and symptom of disorders and provide comfort to the patients. Tablets and capsules are unsuitable for administering with high dose of active pharmaceutical ingredient and since individual large dose is difficult to swallow or require the administration of several tablets or capsule at a time, making it less patient compliant. Also chewable tablets are also not ideal with pediatric and geriatric patients due to need of chewing, poor taste masking and lack of control release possibility. Oral drug delivery is most preferred route of drug delivery [1, 2]. Oral liquid suspensions are majorly designed for the patients with difficulty in swallowing. Sustained release dosage forms aimed at controlling the rate of release as well as maintaining desire drug leve ls in the blood for long duration of time. An oral suspension could be the best suitable dosage form for geriatric and pediatric patients. They include improvement of the rate and extent of drug absorption, higher patient compliance, reduction of side effects and taste masking of bitter drug [3, 4]. There are several of approaches to design and development of sustained release suspension of variety of drugs. Formulation of sustained release suspension will be benefited to avoid fluctuations in blood drug plasma concentration and gives its action for an entire period of time [5, 6]. Linezolid is poorly water soluble drug (3 mg/ml) of BCS class II. Linezolid is an neutral drug and it has a short half- life, due to which it requires frequent administration to maintain the therapeutic effect for a long period of time and also it is not sustained to own due to short half- life, so sustained release formulation are formulated. Linezolid has low plasma protein binding (approximately 31%, but highly variable) and apparent volume of distribution at steady state of around 40-50 liters. Peak serum concentrations are reached up to one hour after administration of drug. Linezolid is readily distributed to all tissues in the body apart from bone matrix and white MATERIALS AND METHODS
Materials
Linezolid was obtained as a gift sample from Cadila healthcare Ltd., Ahmadabad, India. Eudragit RS100 and Eudragit RL100 were obtained as gift sample from Evonic Degussa, India. Ethyl cellulose, Xanthan gum, Acacia and Gaur gum were obtained as gift sample from Finar chemicals, Mumbai, India. All others reagents and chemicals used were of analytical reagent Preparation of Microcapsules and Reconstitutable Sustained Release Suspension
Microcapsules were prepared by spray drying technique using varying ratios of drug and polymers in 1:1, 1:2 and 1:3 ratios like (Eudragit RS100, Eudragit RL100 and Ethyl cellulose) and the effects of various polymers on release of drug from microcapsules were studied by constant feed flow rate 5ml/min. Preliminary study formulas of all different microcapsule formulation of linezolid are listed in Table 1.
Reconstitutable SR suspensions were prepared using optimize batch of microcapsules mixed with various suspending agent (xanthan gum, acacia, gaur gum), Sweetener (sucrose), preservative (Na benzoate), buffering agent (citric acid) and flavoring agent (cherry). Optimize batch formulas of all different reconstitutable sustained release suspension formulations of linezolid are listed in Table 2. Table 1. Microcapsules Formulations of Linezolid (F1-F9)
Batch code
Feed flow
Table 2. Composition of reconstitutable sustained release suspension formulations
Ingredient
1380 1380 1380 1380 1380 1380 1380 1380 Citric acid (buffering * The entire ingredient is taken in the mg and in % w/w of microcapsule * 1380 mg microcapsule contain equivalent to 600 mg of linezolid Optimization of Variable Using Factorial Design
A 32 randomized full factorial design was used in the present study. In this design, 2 factors were evaluated; each 3 levels and experimental trials were performed for all 9 possible combinations (Table 5). The polymer concentration (X1) and feed flow rate (X2) were chosen as independent variable in 32 full factorial design (Table 4), while percentage yield, particle size and encapsulation efficiency were taken as dependent variables (Table 3). A 32 randomized full factorial design was used in development o f dosage form. A statistical model incorporating interactive and polynomial terms was utilized to evaluate the response. Y = dependent variable b0 = arithmetic mean response of the 9 runs bi =estimated coefficients for the factor Xi The main effect (X1andX2) represents the average result of changing one factor at a time from its low to high value. The interaction term (X1X2) shows how the response changes when two factors are change simultaneously. The polynomia l terms (X1X1, X2X2) are included to investigate nonlinearity [7]. Table 3. List of Independent Variables and Dependent Variables
Independent Variables:
Polymer Ratio (X1) Feed flow rate (X2) Dependent Variables:
Time required for 90% drug release (t90) Microencapsulation efficiency (%) % drug release after 6 hrs (Q6) Mean Particle size Diffusion coefficient (n) Time required for 50% drug release (t50) Release rate constant (k) Table 4. Coded value and independent variable
Coded value
Selection of level of independent
variable
X1 (polymer ratio) X2 (feed flow rate) * X1=Polymer ratio *X2=Feed flow rate Table 5. Coded value and uncoded value
Coded value
Uncoded value
Validation of Experimental Design
1. Percentage relative error or bias
To assess the reliability of the model, a comparison between the experimental and predicted values of the responses is also presented in terms of % bias (relative error %). The formula for calculation of % bias or % relative error is as follows: predicted value − actual value It is calculated from the equation Y= Y is the predicted response b0= arithmetic mean response of the 9 runs bi=estimated coefficients for the factor Xi Predicted responses are calculated from the above formula with the help of X1 and X2 variable from table no. 4.16 and actual response are taken from the experimental work. 2. Check point batch
Polynomial equations were generated using Statistica 8.0 for selected responses like % yield, particle size, encapsulation efficiency, Q6.Q8, t90%, Exponential constant (n) and release rate constant (k).The generated polynominal equations were further reduced on the basis of significant terms obtained by applying ANOVA. The design was validated by preparing an extra check point formulation. The predicted values for response were determined on the basis of respective polynomial equations whereas the experimental values were determined by evaluating formulation for dependent variable. The predicted and experimental values of responses were compared for statistical significance using paired t –test [8, 9]. Physical Characterization of Microcapsule
The prepared microcapsules were evaluated for the flow properties, such as loose bulk density, tapped density, carr's index, Hausner ratio and angle of repose [10-13]. Evaluation of Microcapsule
1. Mean Particle size determination by microscopic method
Binocular microscope was used for the particle size at 100 magnifications Particle size observed in ocular scale (µm) [14]. 2. Particle size and shape by Scanning Electron microscopy
The surface topography of the microcapsule was investigated by SEM. Scanning electron microscopy (SEM) photographs were taken using a scanning electron microscope (JSM-5610, Japan) at room temperature. Samples were fixed on a scanning electron microscope sample holder with a double-sided adhesive tape and coated with a layer of gold of 1.5 × 10–10 m for 2 min using a sputter coater (Edwards 3-150 Å, England) in a vacuum of 30.4 kPa of argon gas. Photographs were observed for morphological characteristics and to confirm the spherical nature of microcapsule [15]. 3. Morphological studies of microcapsule by simple binocular microscope
Morphological characteristic of microcapsule of the preliminary and factorial batches are determined by the simple binocular microscope. Spray dried microcapsule are taken on the glass slide and determine the morphological character o f the microcapsule under the simple binocular microscope. Samples of spray dried microcapsule were selected randomly. 4. Percentage yield
The percentage of production yield (wt/wt) was calculated from the weight of dried microcapsule (W1) recovered from each of batches and the sum of the initial dry weight of starting materials (W2). The formula for calculation of percentage yield is as follows [16]. Weight of dried microcapsules W1 total Weight of drug and polymer W2 5. Drug loading
Drug loading are calculated of the microcapsule by weighting the microcapsule after spray drying with polymer and drug to the total quantity of drug taken before spray drying [16]. Weight of drug loaded in microcapsule Total weight of microcapsule 6. Encapsulation efficiency
To estimate linezolid content, drug loaded microcapsule were weighted and crushed properly in mortar and pestle. Briefly 200 mg of each batch of linezolid- loaded microcapsule were crushed and then dissolved in 100 ml of phosphate buffer 7.2 pH. The above solution was kept on sonicator for 3 to 4 hours to get maximum drug released from microcapsule into solution. Then phosphate buffer containing drug was filtered through whattman filter paper to remove any polymer debris. The clear solution obtained was analyzed using UV spectrophotometer at ƛ max value of 251 nm using pure phosphate buffer as blank [17]. The % Encapsulation efficiency of linezolid microcapsule was calculated using formula as follows % Encapsulation efficiency = % Theoretical loading 7. Drug Content Uniformity
Weight accurately the 200mg microcapsule which contains 100 mg equivalent weight of linezolid and then transferred to 100ml of 7.2 pH Phosphate Buffer containing volumetric flask and kept on sonicator for 3-4 hours to get maximum drug release from microcapsule into solution. The solution was analyzed at 251nm using double beam UV-Visible spectrophotometer after suitable dilution. The content of drug was calculated from calibration curve [18]. 8. In-vitro drug release study
The In-vitro drug release was performed using USP 24 type II paddle apparatus using 700 ml of 0.1 N HC1 at 50 rpm at 37±0.5°C for first two hours. The samples were withdrawn at predetermined time intervals for period of 2 hr and replaced with the fresh medium. After 2 hours that add the 200 ml solution of tri-sodium phosphate to replace the pH 1.2 to 7.2 and sample are withdrawn at predetermined time intervals for remaining 10 hrs. The samples were filtered through whattman filter paper; suitably diluted and analyzed at 251nm using double beam UV- Visible spectrophotometer. The content of drug was calculated using calibration curve. Evaluation Parameter of Reconstitutable Suspension
1. Organoleptic property
Prepared formulation with different excipient was observed for colour, odour and appearance and it was found properly mixed. The pH of reconstitutable suspension was determined by using digital pH meter (Welltonix digital pH meter PM100). 3. Viscosity
The viscosity of suspension was determined by Brookfield viscometer ( Brookfield Eng. Lab). In adapter 40 ml of suspension was taken and the adapter is set over the viscometer by a stand such a way that spindle is completely immersed in the suspension. Spindle number 3 was used. 4. Sedimentation volume
Take 10 ml of each suspension was taken in 50 ml stopper graduated measuring cylinder. The suspension was dispersed thoroughly by moving upside down for three times. Later, the suspension was allowed to settle for three minutes and the height of sediment was noted. This was the original height of sediment (H0). The cylinder was kept undisturbed for 7 days. The height of sediment read at every 24 hr for 7 days was considered as final height of sediment Sedimentation volume (F) = Hu/H0 The ultimate height of the solid phase after settling depends on concentration of solid content. To obtain an acceptable suspension, F should be at least 0.9 for 1hour but a longer period was preferred for our purpose and F value means sedimentation volume was measured to check the physical stability of the suspension. It can have values nearly 1. 5. Redispersibility
Fixed volume of each suspension (10 ml) was kept in stoppered cylinder which was stored at room temperature for 7 days. The redispersibility was determined by studying number of stocks to redisperse the formed sediment at the end of 7 days of storage of the formulation [19, 20]. Accelerator Stability Study
The purpose of stability testing is to provide evidence on how the quality of drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a re-test for the drug substance or a shelf life for the drug product and recommended storage condition. The storage condition used for stability studies were accelerated condition 400 C ± 20 C / 75 % ± 5% RH for the optimized formulation of reconstitutable sustained release suspension [21]. RESULT AND DISCUSSION
Drug Excipient Compatibility Study
Fig. (1). Compatibility study of drug with excipients
Fourier transform infrared spectroscopy has been used to study the physical and chemical interactions between drug and Excipients used in the formulation. Fourier transform infrared (FTIR) spectra of Linezolid, Eudragit RS100, Sucrose, Xanthan gum, citric acid and sodium benzoate were recorded using Potassium bromide (KBr) mixing method and there was not found any kind of interaction between drug, polymer and other excipie nt and it spectra of drug and excipient compatibility are showed in the Figure 1 and Table 6. Table 6. Functional Group and Frequency of Drug with Excipient
Functional group
Frequency of Pure Drug (cm-1)
1143.83, 1274.99 FTIR peaks observed in the linezolid and excipient sample mixture were found to be 1274.99 cm-1, 1143.83 cm-1, 1357cm-1, 1516 cm-1, 906.57 cm-1, 756.12 cm-1, 680.89 cm-1. Characterization of Microcapsule
1. Physical Characterization of Microcapsule
The angle of repose for the microcapsule was carried out after spray drying and results were reported that the batches F1, F2,F3,F6 has a value between 20° to 30°, which shows good flow property and batches F4, F5, F7, F8, and F9 shows range between 300 to 340, Which shows the passable flow property. Compressibility index for the microcapsule was carried out after spray drying and results were reported that the batches F1, F2, F5 have a range between 11-15 so, it shows good compressibility index, batches F3, F4, F6, F7, F9 have a range between 16-20 so, it shows fair compressibility index and batches F8 have a range between 21-25 so, it shows the passable compressibility index. Hausner's ratio for the microcapsule was carried out after spray drying and results were reported that the batches F1, F2, F3, F5 have a range between 1.12-1.18 so, it shows good flow property, batches F4, F6, F7, F8, F9 have a range between 1.19-1.25 so, it shows a fair flow property. In the preliminary screening of the batches F1 to F9 have a physical characteristics of microcapsules in the acceptable range and all the result of Physical Characterization of Microcapsules of preliminary batches (F1-F9) are depicted in Table 7. Table 7. Physical Characterization of Microcapsule (F1 -F9)
Bulk density
Tap density
Hausne r's Angle of repose
2. Evaluation of Microcapsule
In the preliminary study, the microcapsule batches were evaluated for % practical yield,
encapsulation efficiency, % drug loading, mean particle size and surface morphology. The % practical yield, encapsulation efficiency and mean particle size are increased with increase to drug to polymer ratio and drug loading are decreased with increase to drug to polymer ratio. Hence, batch F3 show high % practical yield, encapsulation efficiency and particle size. Sustained release suspension was prepared for the 12 hours so, F1 batch are optimized for further factorial analysis with different polymer ratio and different feed flow rate (Table 8). Table 8. Evaluation of Microcapsule (F1-F9)
Practical yield
Drug loading
Mean Particle
efficiency (%)
Size (µm)
3. In-Vitro Drug Release of Preliminary Batches of Microcapsule
In the present research work, formulation of preliminary batches F1 to F3 use Eudragit RS100 in varying concentration, (1:1, 1:2, 1:3) for preparation of microcapsule by spray drying technique and it was reveal that as concentration of drug to polymer is increases with increase the drug release. F1 batches shows drug release up to 98.94 % within 10 hours whereas the formulation batches F2 and F3 shows the drug release up to 96.89 % and 83.98 % within 12 hours, respectively. Results were depicted in table 9 and figure 2. Table 9. In-Vitro Drug Release of Preliminary Batches (F1-F9) of Microcapsule.
36.88 23.75 22.55 47.89 39.09 36.18 36.08 35.75 33.47 47.32 27.19 23.25 59.09 44.02 42.07 44.67 42.71 39.47 57.42 35.99 27.31 61.07 53.66 49.44 53.61 47.24 43.79 64.66 46.81 30.73 77.97 59.85 55.23 62.55 51.67 49.33 76.96 53.45 34.40 86.97 63.51 59.11 73.28 58.46 55.99 81.46 67.84 38.09 91.84 76.68 64.89 85.08 63.11 59.94 87.80 74.95 46.48 98.89 79.66 67.81 91.49 69.55 64.45 92.51 79.21 57.48 89.07 73.55 98.71 73.26 67.45 97.21 83.78 66.67 98.94 88.10 72.87 In formulation batches F4 to F6 use the Eudragit RL100 in varying concentration, (1:1, 1:2 and 1:3) for preparation of microcapsule it was justify that as concentration of polymer is increases with increase the drug release. F4 batches shows drug release up to 98.89% within 7 hours while the formulation batches F5 and F6 shows the drug release up to 98.91% and 93.74% within 11 and 12 hours, correspondingly. Results were depicted in table 9 and figure 2. In formulation batches F7 to F9 using ethyl cellulose in varying concentration, (1:1, 1:2 and 1:3) for preparation of microcapsule it was justify that as concentration of polymer is increases with increase the drug release. F7 batches shows drug release up to 98.71% within 8 hours even as the formulation batches F8 and F9 shows the drug release up to 92.37% and 89.14%, in that order. Results were depicted in table 9 and figure 2. From all the batches of microcapsule (F1 to F9), F1 batch exhibit excellent and uniform drug release up to 98.94 % within 10hours, So Eudragit RS100 (1:1) ratio was use for optimization of In the preliminary study other batches are also show drug release at 11 and 12 hours. Here F5 batches show drug release at the 11 hours 98.91% but here drug to polymer ration are 1:2. So, finally bulky volume of reconstitutable suspension are increased and it not comfortable to the Hence main goal to prepare reconstitutable sustained release suspension is, in the low drug to polymer ratio it give a sustained action till to 12 hours and it may too comfortable to the patient to take orally. So, here F1 batches are optimized for further factorial design to using 1:1.1, 1:1.2 and 1:1.3 drug to polymer ratio and 5, 10, 15 ml/min feed flow rate. Batch Code
Fig. (2). CPR of the preliminary batches (F1-F9) batches
This figure 2 indicates that with increase the drug to polymer ratio drug release rate are Evaluations of Factorial Batches of Microcapsule
Physical characte rization of factorial batches of Microcapsule
Cars index of factorial batches are showed in the table 10. Here batches S1, S2, S3, S4, S5, S6 and S9 has a range between 11 to 15 so, it show good compressibility index and S7 and S8 has a range between 16 to 20 so it show a fair compressibility index. Hausner's ratio of factorial batches are showed in table 10 and here batches S1, S2, S3, S4, S5, S6, S7 and S9 has a range of hausner's ratio between 1.2 to 1.8 so, it show a good flow property and batch S8 show a range between 1.19 to 1.25 so, it show a fair flow property. Table 10. Physical characterization of factorial batches (S1-S9)
Bulk density Tap density Carr's Hausne r's Angle of
Drug loading
Angle of repose of a factorial batches showed in the table 10. here batches S1, S2, S3, S4, S5, S6, S8 and S9 has a range of angle of repose between 20 to 30 so, it show a good flow property and batch S7 show a range between 30 to 34 so, it show a passable flow property. 5.3.1 Evaluations of Factorial Batches of Microcapsule
Ideal values of the percentage practical yield, percentage encapsulation efficiency and mean particle size are showed in the table 11. The practical yields are increase with the increase the polymer ratio, but it may be decrease with increase the feed flow rate. But the percentage encapsulation efficiency is also increase with increase the polymer ratio, where as it may also decrease with increase the feed flow rate. Particle sizes of the factorial batches are increase with increase the polymer ratio and the feed flow rate. In present research work,S3 batch are optimized for preparation of the reconstitutable sustained release suspension because it has a high percentage yield (87.82) and percentage encapsulation efficiency (99.07), 16.06 µm mean particle size and smooth surface and spherical shape. Table 11. Evaluations of factorial batches of Microcapsule
Practical Yield
Mean Particle Drug loading
Efficiency (%)
size(µm)
5.3.2 In-Vitro Drug Release of Factorial Batches of Microcaps ule
In the factorial batches Eudragit RS 100 are used in the different concentrations with the different feed flow rate. In-vitro drug release profile of the factorial batches are showed in the table 12 and result indicate that drug release time are increased with increase the drug to polymer concentration and feed flow rate. From the study of factorial design, batch S3 are optimized for the preparation of reconstitutable suspension because it show maximum cumulative percentage drug release up to 99.12% within 12 hours as compare to other batches. Table 12. In-vitro drug release of factorial batches of Microcapsule
37.25 35.67 39.75 45.83 43.55 45.63 52.64 47.35 50.64 60.37 54.64 62.53 67.25 63.64 70.46 73.56 72.18 75.34 79.38 77.68 80.45 84.37 83.57 86.66 91.65 89.08 93.56 95.34 92.14 97.09 Batch Code
Fig. (3). CPR of the factorial batches S1 to S9
This figure 3 indicates that drug release rate are decreased with increase the drug to polymer ratio and feed flow rate. Statistical Analysis of Factorial Batches
All batches contained microcapsule which contains drug (linezolid) and polymer (Eudragit RS100) in a different ratio. In 32 full factorial design here takes independent variable X1 (polymer ratio like 1:1.1, 1:1.2, 1:1.3) and X2 (feed flow rate 5, 10, 15 ml/min). A 32 full factorial design was designed to study the effects of the polymer ratio and feed flow rate (ml/min) of spray dryer on the percentage yield, mean particle size, encapsulation efficiency, Q 6, Q8, t90, diffusion exponent (n) and release rate constant (k) of microcapsule. The result of analysis of variance test for all three effects indicated that the test is significant (Table 13). Table 13. Result of dependent variables
Batch Variable
Diffusion
Particle
Encapsulation (%)
(hr) Exponent
Efficiency
constant
79.01 93.88 7.47 73.04 86.79 8.465 0.428 66.43 78.25 9.988 0.4317 75.85 89.71 8.040 0.4082 71.44 83.18 8.999 0.4245 68.91 79.64 9.766 0.441 69.96 81.41 9.49 66.69 77.26 10.40 0.3965 63.78 74.34 10.96 0.4137 A statistical model incorporating interactive and poly nominal terms used to evaluate the Y =b0 + b1X1 + b2X2+ b11X1X1 + b22X2X2+ b12X1X2
Where, Y is the dependent variable, b0 is the arithmetic mean response of 9 runs, and b1 is the estimated coefficients for the factor X1.The main effect (X1 and X2) represents the average result of changing one factor at a time from its low to high value. The interaction term (X1X2) shows how the responses changes when two factors are change simultaneously. The polynomial terms (X1X1, X2X2) are included to investigate nonlinearity. Analysis of variance (ANOVA) was performed to identify insignificant factors. Data were analyzed using Microsoft Excel software. The reduced models were developed for response variables by removing the insignificant terms with P more than 0.05. The terms with P less than 0.05 were considered statistically significance and retained in the reduced model. 1. Full and re duced model for % yield
Y1 = 85.72+ 1.00X1- 1.23X2- 0.19X1X1- 0.20X2X2+ 0.13X1X2
Response plot indicate that the positive effect of polymer ratio on the percentage yield. The response observed for this effect is of linear type. With increase in the polymer ratio, the percentage yield also increases due to the increase throughput of the polymer slurry and rapid evaporation of the solvent. Response surface plot also indicates the negative effect of feed flow rate on the percentage yield. The response observed for this effect is also of linear type. With increase in the feed flow rate, the value of percentage yield increases due to the incomplete atomization and drying, resulting in the deposition of a large amount of microcapsules on the walls of the desiccating chamber and the cyclone separator. The significance level of coefficients b11, b22and b12 was found to be greater than P=0.05, thus they were omitted from the full model to generate the reduced model. The results of statistical analysis are shown in table 14. The coefficients b1 and b2 were found to be significant at P <0.05, thus they were retained in the reduced model. The reduced model was tested in portions to determine whether the coefficients b1 and b2 contribute significant information for the prediction of % Yield. The results of testing the model in portions are shown in Table 15 and figure 4. Polymer ratio at higher level (X1, +1) and feed flow rate at lower level (X2, -1) yielded microcapsules with higher percentage yield. Table 14. Summary of results of regression analysis for % Yield
Response %
1.84E-07 0.0163 0.0092 0.6188 0.6103 0.6409 Table 15. Calculation for testing the models in proportions for % Yield
Regression
Residual
Fig. (4). Response surface plot of % yield
2. Full and re duced model for Mean particle size (µm)
Y2 = 17.37 + 1.43X1 + 1.93X2- 0.12X1X1 - 0.395X2X2- 0.055X1X2
When considering second response in term of particle size (Y2), interaction terms are insignificant. Response surface plot indicates the negative effect of drug to polymer ratio the particle size. The particle size of the microcapsule decreases with decrease the drug to polymer ratio or increase with increase the drug to polymer ratio and it may be increased due to increased viscosity of the feed solution which influence the interaction between disperse phase and dispersion medium that affects the size distribution of particle. Response surface plot indicates negative effects of feed flow rate. This may be due to a higher feed flow rate the atomizing air may not be able to penetrate the stream of liquid. As a result, incomplete atomization may lead to wider droplet size distribution. The significance level of coefficients b11, b22 and b12 was found to be greater than P=0.05, thus they were omitted from the full model to generate the reduced model. The results of statistical analysis are shown in Table 16. The coefficients b1 and b2were found to be significant at P <0.05, thus they were retained in the reduced model. The reduced model was tested in portions to determine whether the coefficients b1 and b2 contribute significant information for the prediction of particle size (µm). The results of testing the model in portions are shown in Table 17 and figure 5. Drug to polymer ratio at lower level (X1, -1) and feed flow rate at lower level (X2, -1) yielded microcapsule with smaller particle size. Table 16. Summary of results of regression analysis for Mean particle size (µm)
Response
Particle size (µm)
-0.055 0.973 0.014 3.19E-05 0.0085 0.0036 0.7847 0.3980 0.8588 Table 17. Calculation for testing the models in proportions for Mean particle size (µm)
Regression
Residual
Fig. (5). Response surface plot of Mean particle size
3. Full and re duced model for Encapsulation efficiency (%)
Y3 = 97.89+ 0.89X1- 0.656X2- 0.306X1X1 + 0.1933X2X2+ 0.25X1X2
When considering the response term of encapsulation efficiency, the response surface plot indicates the positive effect of drug to polymer ratio on the response term. The encapsulation efficiency of the microcapsule increase with increase in the drug to po lymer ratio, due to amount of drug remaining and available for encapsulation increases as theoretical drug loading increases. Consequently, the actual drug loading increases. As the molecular weight of the polymer increased, its hydrophobicity increased, leading to better precipitation of polymer at the boundary phase of the droplets. Response surface plot indicates negative effect of feed flow rate on the encapsulation efficiency; it may be due to that the high pumping rates during the spray drying process result in large volumes of nebulized solutions to be dried. Owing to this heated air may not instantaneously transform the liquid droplets into solid microcapsules, leading to the formation of larger, irregular particles that are not completely dried and hence resulting in decrease in encapsulation efficiency. The results of testing the model in portions are shown in Table 18 and 19 and figure 6. Drug to polymer ratio at higher level (X1, +1) and feed flow rate at lower level (X2, -1) yielded microcapsule with higher percentage encapsulation efficiency. Table 18. Summary of results of regression analysis for Encapsulation efficiency (%)
Response
efficiency (%)
1.67E-08 0.0034 0.0083 0.1915 Table 19. Calculation for testing the models in proportions for Encaps ulation efficiency
Regression
Residual
Fig. (6). Response surface plot of Encapsulation efficiency (%)
4. Full and re duced model for the Q6 (%)
Y4 = 71.88- 4.28X1- 3.00X2+ 0.266X1X1 - 2.24X2X2+ 1.6X1X2
Here negative value of the X1(drug: polymer ratio) variable indicate that the Q 6is decrease with respect to increase the polymer ratio. Here negative value of the X2(feed flow rate) variable indicate that the Q 6 is decrease with respect to increase the feed flow rate. When drug to polymer ratio and feed flow rate are increase, so there is increase size of particle and with respect to increase the particle size there is increase the time of cumulative percentage drug release with respect and According to Noyes Whitney equation the rate of dissolution is directly proportional to surface area of powdered drug that means higher surface area (very small the particle size), higher the rate of dissolution. If surface area of powdered drug is lower that means lower the rate of dissolution of powdered drug and higher the time of cumulative percentage drug release. Increase the particle size there is increase the time of drug release that means quantity of drug release is increase with increase in the drug to polymer ratio and feed flow rate. The results of testing the model in portions are shown in Table 20 and 21 and figure 7. Table 20. Summary of results of regression analysis for Q6 (%)
Response Q6
Table 21. Calculation for testing the models in proportions for Q6 (%)
Regression
Residual
Fig. (7). Response surface plot of the Q6 (%)
5. Full and re duced model for the Q8 (%)
Y5 = 83.86- 5.46X1- 4.31X2+ 0.46X1X1 - 2.18X2X2+ 2.14X1X2
Here negative value of the X1(drug: polymer ratio) variable indicate that the Q 8 is decrease with respect to increase the polymer ratio. Here negative value of the X2(feed flow rate) variable indicate that the Q 8 is decrease with respect to increase the feed flow rate. When drug to polymer ratio and feed flow rate are increase, so there is increase size of particle and with respect to increase the particle size there is increase the time of cumulative percentage drug release with respect and According to Noyes Whitney equation the rate of dissolution is directly proportional to surface area of powdered drug that means higher surface area (very small the particle size), higher the rate of dissolution. If surface area of powdered drug is lower that means lower the rate of dissolution of powdered drug and higher the time of cumulative percentage drug release. Increase the particle size there is increase the time of drug release that means quantity of drug release is increase with increase in the drug to polymer ratio and feed flow rate. The results of testing the model in portions are shown in Table 22 and 23 and figure 8. Table 22. Summary of results of regression analysis for Q8 (%)
Response Q8 (%)
9.8E-07 0.0005 0.0011 0.502 0.036 0.015 Table 23. Calculation for testing the models in proportions for Q8 (%)
Regression
Residual
Fig. (8). Response surface plot of the Q8 (%)
6. Full and re duced model for the t90 (hr)
Y6 = 8.93 + 0.950X1 + 0.823X2- 0.001X1X1 + 0.531X2X2- 0.260X1X2
Here positive value of the X1(drug: polymer ratio) variable indicate that the t90 (hr) is increase with respect to increase the polymer ratio. Here positive value of the X2(feed flow rate) variable indicate that the t90 (hr) is increase with respect to increase the feed flow rate. When drug to polymer ratio and feed flow rate are increase, so there is increase size of particle and with respect to increase the particle size there is increase the time of cumulative percentage drug release with respect and According to Noyes Whitney equation the rate of dissolution is directly proportional to surface area of powdered drug that means higher surface area (very small the particle size), higher the rate of dissolution. If surface area of powdered drug is lower that means lower the rate of dissolution of powdered drug and higher the time of cumulative percentage drug release. Increase the particle size there is increase the time of drug release that means quantity of drug release is increase with increase in the drug to polymer ratio and feed flow rate. The results of testing the model in portions are shown in Table 24 and 25 and figure 9. Table 24. Summary of results of regression analysis for t90 (hr)
Response t90 (hr)
0.531 -0.2607 0.990 0.0030 7.5E-06 0.0010 0.0015 0.9912 Table 25. Calculation for testing the models in proportions for t90 (hr)
Regression
Residual
Fig. (9). Response surface plot of the t90 (hr)
7. Full and re duced model for the diffusion exponent (n)
Y7= 0.4243+ 0.012X1- 0.012X2+ 0.0003X1X1 - 0.012X2X2+ 0.00215X1X2
Here positive of the X1(drug: polymer ratio) variable indicate that the diffusion constant is increase with respect to increase the polymer ratio. Here negative value of the X2(feed flow rate) variable indicate that the diffusion constant is decrease with respect to increase the feed flow rate. The significance level of coefficients b11 and b12 was found to be greater than P=0.05, thus they were omitted from the full model to generate the reduced model. The results of statistical analysis are shown in table 26. The coefficients b1, b2 and b22 were found to be significant at P <0.05, thus they were retained in the reduced model. The reduced model was tested in portions to determine whether the coefficients b1, b2 and b22 contribute significant information for the prediction of diffusion exponent (n). The results of testing the model in portions are shown in Table 27. The critical value of F for α = 0.05 is equal to (DF=2, 3). Since the calculated value (F=0.341) is less than the critical value (F=9.55), it may be concluded that the omitted term do not contribute significantly to the prediction of diffusion exponent (n). The results are shown in the form of response surface plot in figure 10. Table 26. Summary of results of regression analysis for diffusion exponent (n)
Response
diffusion
exponent (n)
0.0003 -0.012 0.00215 0.963 1.71E-06 0.0107 0.009 Table 27. Calculation for testing the models in proportions for diffusion exponent (n)
Regression
Residual
Fig. (10). Response surface plot of the diffusion exponent (n)
8. Full and re duced model for the release rate constant (k)
Y8 = 0.3481- 0.024X1- 0.004X2- 0.0004X1X1 - 0.0014X2X2+ 0.0038X1X2
Here negative value of the X1(drug: polymer ratio) variable indicate that the release rate constant is decrease with respect to increase the polymer ratio. Here negative value of the X2(feed flow rate) variable indicate that the release rate constant is decrease with respect to increase the feed flow rate. The significance level of coefficients b11 and b22 was found to be greater than P=0.05, thus they were omitted from the full model to generate the reduced model. The results of statistical analysis are shown in table 28. The coefficients b1, b2 and b12 were found to be significant at P <0.05, thus they were retained in the reduced model. The reduced model was tested in portions to determine whether the coefficients b1, b2 and b12 contribute significant information for the prediction of release rate constant (k). The results of testing the model in portions are shown in Table 29. The critical value of F for α = 0.05 is equal to (DF=2, 3). Since the calculated value (F=0.434) is less than the critical value (F=9.55), it may be concluded that the omitted term do not contribute significantly to the prediction of release rate constant (k). The results are shown in the form of response surface plot in figure 11. Table 28. Summary of results of regression analysis for release rate constant (k)
Response release
rate constant (k)
-0.004 -0.0004 -0.0014 0.0038 0.996 0.0008 2.51E-07 0.0001 0.0188 0.003 0.994 3.69E-06 Table 29. Calculation for testing the models in proportions for release rate constant (k)
Regression
Residual
Fig. (11). Response surface plot of release rate constant (k)
Kinetic Modeling of Dissolution Data
The kinetics of the dissolution data were well fitted to zero order, Higuchi model and Korsemeyer-Peppas model as evident from regression coefficients (table 30). The value of diffusion exponent (n) for S1 to S9 factorial formulations was between 0.3585 to 0.4317 so it indicates Fickian diffusion of the drug from formulation which corresponds to diffusion, erosion and swelling mechanism. Kinetic model Higuchi indicating that R2 value of S1 to S9 was between 0.981 to 0.998 shows that drug release type was diffusion type from gel network and extended drug release for longer period of time. Kinetic Model Zero order indicating that R2 value of S1 to S9 was in range 0.981 to 0.999 that near about 1.000 clearly mentioned that drug release from stiff gel networking was Zero order drug release that not depend on concentration of drug. Kinetic Model First order indicating that R2 value of S1 to S9 was between 0.956 to 0.986 that having less than Zero order release R2 value, mentioned that drug release type was not first order release from gel network (Table 30). Table 30. Kinetic Modeling of Dissolution Data
Parameters
Ze ro order
First order
Hixon Crowe ll
-1.827 -1.605 -1.600 -0.991 -0.998 -0.984 -0.981 -0.998 -0.995 -0.995 Korsemeyer and Peppas
-0.439 -0.491 -0.386 -0.440 -0.456 -0.414 -0.446 -0.471 S= slope, I= intercept, R2= square of correlation coefficient, n= diffusion exponent
Comparison of Dissolution Profiles For Selection of Optimum Batch
The values of Dissimilarity factor (f1) for batches S2, S3, S5, S6, S7, S8, and S9 were less than 15 compared with theoretical dissolution profile indicating good similarity in dissolution. The batch S3 showed minimum value of f1 (2.90). The values of similarity factor (f2) for batches S2, S3, S5, S6, S7, S8, and S9 were greater than 50 compared with theoretical dissolution profile indicating good similarity in dissolution. The batch S3 showed maximum value of f2 (82.35). Similarity Factor (f2) and Dissimilarity factor (f1) for S1-S10 are showed in table 31. Table 31. Similarity Factor (f2) and Dissimilarity factor (f1) for S1-S9
Similarity factor (f2)
Dissimilarity factor (f1)
Validation of Experimental Design
1. Percentage relative error or bias
Reliability of the generated models was studied by comparing the experimental and predicted values in terms of % bias. Low values of % bias for all responses shows a good agreement between the experimental and predicted values (Table 32, 33 and 34). The result of analysis of variance test for both effects indicated that the test is significant. Table 32. Actual response, predicted response and % bias obtained for the studied
parameters percentage yield, mean particle size, encapsulation efficiency
Mean particle size
% Encapsulation
efficiency
Predicted Actual
Predicted Actual
Predicted Actual
Table 33. Actual response, predicted response and % bias obtained for the studied
parameters Q6, Q8, t90
Predicted Actual
Predicted Actual
Predicted Actual
Table 34. Actual response, predicted response and % bias obtained for the studied
parameters Diffusion Exponent (n) and Release Rate constant (k)
Diffusion Exponent (n)
Release Rate constant (k)
Predicted
Predicted
2. Check point batch
The 32 factorial designs were run with one check point composition of which is shown in Table 35. Batch CP1 was prepared to validate the derived equation for Evaluation parameter and in- vitro dissolution time of microcapsule with one check point composition. The data for Evaluation parameter and in vitro dissolution time for the predicted and observed values are shown in table It can be observed that the predicted value and observed value for CP1 for Evaluation parameter and in-vitro dissolution time of microcapsule were nearly similar with 32 factorial designs batches. It can be concluded that the evolved model can be used for prediction of response i.e. Evaluation parameter and in-vitro dissolution time of microcapsule within the simplex space. Comparative analysis of the predicted value and experimental value using paired t– test indicated that there was no significant difference between the two values thereby establishing validity of generated mode. In this research work between the tstat (1.36) and tcri (2.44) not significant difference and tcri value very high as compare to tstat. In the present research work, no very much difference between factorial batches and one check point composition and percentage relative error small between predicted and experimental value. Table 35. Composition and Evaluation parameter and in-vitro dissolution of check point
Evaluation parameter
Mean particle
% Encapsulation
Check point batch (CP1)
efficiency
X1 = -0.5; X2 = +0.5; X3 =7.5
In-vitro dissolution study
Check point batch (CP1)
X1 = -0.5; X2 = +0.5; X3 =7.5
Check point batch (CP1)
In-vitro dissolution study
Exponential constant (n)
Release rate constant (k)
X1 = -0.5; X2 = +0.5; X3 =7.5
* P= Predicted value; O = Observed value
Morphological Studies of Microcaps ules
By simple microscope
The surface topography of the microcapsule was investigated by simple binocular microscope. As seen in figure 12, they were spherical in shape and exhibited porous surface. Fig. (12). Morphological Characte ristics of Microcapule by simple microscope
SEM analysis of the microcapsule
SEM of drugs loaded polymeric microcapsule reveals that the microcapsule possess rough, porous and rugged surface Figure 13. The surface porosity is crucial for drug release in microcapsule prepared, since the polymer is not biodegradable, the release of the drugs from microcapsule take place by dissolution and diffusion through the pores. The most part of microcapsule was small and had spherical shape, non- uniform surface and were coalesced. Fig. (13). SEM analysis of the microcapsule
Evaluation of Reconstitutable Suspension
1. In-vitro dissolution study
Reconstitutable suspension are prepared by using a various suspending agent like xanthan gum, acacia and guar gum and here suspending agent do not have a more effect of the drug release profile of the reconstitutable SR suspension. In the batches no N1-N3 there is use a xanthan gum (2, 3, 4 % w/w), N4-N6 uses acacia (2, 3, 4 % w/w) and in N7-N9 uses a gaur gum (2, 3, 4 % w/w) respectively (Table 36). Table 36. Dissolution profile of Reconstitutable suspension
Time (hrs)
2. Organoleptic property of all formulation
 Colour- White  Odour- odourless  Appearance –white amorphous dry mixture  Flavor- cherry flavour 3. Sedimentation volume
The sedimentation volumes of all the formulations are depicted in table 37. F value means sedimentation volume was measured to check the physical stability of the suspension. It can have values nearly 1. The result showed that formulation batch (N3) having sedimentation of(0.928) after 7 days which is very nearer to the standard value of sedimentation volume 1, so that N3 formulation was better than other. Table 37. Sedimentation rate of the reconstitutable suspension
Height of sediment(cm) after
(Hu) (Hu) (Hu) (Hu) (Hu) (Hu) (Hu)
The pH of reconstitutable suspension was determined by using digital pH meter (Welltonix digital pH meter PM100). All the batches N1-N9 have a pH 7.0, which are neutral and it is show in the table 38. 5. Viscosity
Viscosity of different formulation is shown in table 38. Xanthan gum imparts its high viscosity at low concentration with good ranging flow characteristics, which increase with increasing concentration of suspending agent. In this formulation batch N3 has a high viscosity (697 cP) as compare to other batches. 6. Redispersibility
The Redispersibility of preliminary batches of reconstituted suspension is exhibited in table 38. Redispersibility is an important factor when one has to deal with suspension. As if there is no dispersion of suspension then it will lead to caching of solid content and if caking occurs then there must be chance of non-uniform dose of drug during medication because the drug remains in the cake. Result shows formulation batch N3 had minimum number of strokes 4 as compared to other formulation batch. Table 38. Viscosity, pH and Redispersibility of the reconstitutable suspension
Batch No.
Viscosity (cP)
(No. of Strokes)
Accelerator Stability Studies of Reconstitutable Sustained Release Suspension
Result showed accelerator stability parameter of the prepared formulation batch N3 is depicted in table 39. To obtain acceptable suspension, all parameter have minor differences. Table 39. Accelerator stability studies of the reconstitutable suspension
Evaluation Parameters
After 15 days
Sedimentation volume Redispersibility CONCLUSION
In the present Research work, attempt has been made to design and develop reconstitutable sustained release (SR) suspension of linezolid using spray drying technique for decrease the dosing frequency and suitable for pediatric and geriatric patients. Spray drying technique are used to prepare microcapsule for reconstitutable SR suspension of API (linezolid) and polymer (Eudragit RS100, Eudragit RL100 and Surelease), which are freely soluble in the dichloromethane so it is used as a solvent to prepare microcapsule in the preliminary and factorial batches. From the preliminary study, Eudragit RS100 was exhibited the higher % practical Yield, more encapsulation efficiency, superior mean particle size, uniform drug release for prolong period up to 10 hrs. So, batch F1 are more suitable and used for the preparation further 32 factorial batches. FTIR spectroscopy revealed that there was no chemical interaction between drug and polymer so; it is compatible with drug and polymers. Scanning electron Microscopy showed that microcapsules were spherical with smooth surface. Results was clearly indicated that drug to polymer ratio and feed flow rate had significant influence on percentage yield, mean particle size, encapsulation efficiency, Q6, Q8, t90, Diffusion coefficient (n) and Release rate constant (k). Form the study, the optimized formulation (S3) showed 99.12% cumulative drug release at the end of 12 hrs with drug to polymer ratio (1:1.3) and feed flow rate (5 ml/min) respectively for obtaining the higher percentage of yield, maximum encapsulation efficiency, Particle size of microcapsules which is found to be 87.82%, 99.07% and 16.06 µm consequently. In 32 factorial designs batches were used two independent variable X1(drug to polymer ratio) and X2 (feed flow rate), while percentage yield, mean particle size, encapsulation efficiency, Q 6, Q8, t90, Diffusion coefficient (n) and Release rate constant (k) were taken as dependent variable and in the 32 factorial designs the positive coefficient of X1 in case Y1,Y2, Y3, Y6 and Y7 refers to increase in percentage yield, particle size, encapsulation efficiency,t90 and diffusion exponent (n) with increase in drug to polymer ratio. Similarly, positive coefficient of X2 in case of Y2 and Y6 refers to increase mean particle size and t90 with increase in feed flow rate. While in case of response term Y4, Y5 and Y8, there is negative coefficient of X1 refers to decrease in Q6,Q8 and release rate constant (k) with increase to drug to polymer ratio. Whereas, In case of response term Y3, Y4, Y5, Y7 and Y8, there is negative coefficient of X2 refers to decrease in encapsulation efficiency, Q6, Q8, diffusion exponent (n) and release rate constant (k) with increase to drug to polymer ratio. Low values of % bias for all responses shows a good agreement between the experimental and predicted values. Comparative analysis of the predicted value and experimental value using paired t – test indicated that there was no significant difference between the two values thereby establishing validity of generated mode of Evaluation parameter and in-vitro dissolution time of microcapsule with one check point composition. The results from the estimated ridge of maximum response value of Y1 (percentage yield), minimum response value of Y2 (particle size) and maximum response value of Y3 (Encapsulation efficiency) and cumulative percentage drug release in terms of desirability revealed that optimum drug to polymer ratio (X1) and feed flow rate (X2) were 1:1.3 and 5 ml/min respectively are desirable. From the full factorial design and different graphical representation, it was finalized that batch S3 was found to be optimized batch having drug release up to 12 hr. More ever, the dissolution profile of optimized batch S3 was found to be similar with theoretical drug release profile having similarity factor more than 50 (f2= 82.35) and dissimilarity factor less than 15 (f1=2.90) which reflects the feasibility of the optimization procedure in successful development of sustained release microcapsule by using Eudragit RS 100. Microcapsule prepared with 1:1.3 drug to polymer ratio were selected for SR suspension formulations since they have higher loading efficiency and suitable micrometric properties to disperse in aqueous medium. Reconstitutable SR suspensions were prepared using optimize batch of microcapsules with various suspending agent (xanthan gum, acacia, gaur gum), Sweetener (sucrose), preservative (Na benzoate), buffering agent (citric acid) and flavoring agent From the results of reconstitutable SR suspension, it can conclude that the high sedimentation volume and better redispersibility and high viscosity of the suspend ing agent xanthan gum in a low quantity which more suitable for the optimization of formulation. As the viscosity of suspension was higher the particles or solid contents present in the suspension will not sediment for a longer time. So they will remain s uspended in the suspension. Due to this effect the sedimentation volume of suspension was higher and the sedimentation rate was slow. Redispersibility of higher viscous suspension is also better. This was because of that as the lowest sediments of particles occur it will easily redisperse again. So in present work it was shown that due to high viscosity of xanthan gum (3% w/w), it's the sedimentation volume was highest and redispersibility and viscosity was better than other formulations. Results clearly revealed that drug release studies of SR suspension formulation did not show any statistically significant differences (P>0.05) from the properties of microcapsule alone. Results reported the release profiles of suspension prepared from microcapsules no significant difference (P>0.05) was observed in cumulative percentage drug release for sustained release suspension on 1day and after 15days which indicates the suspension stability. Finally, it was concluded that the type of polymer and feed solution of the spray dryer had a major impact on the in vitro release of drug from microcapsules and suspensions and it can be precise dosing of drug, patient compliance and suitable for pediatric and geriatric intended sustained release of drug up to 12 hrs. CONFLICT OF INTEREST
The author declares no conflict of interest. Authors acknowledge to Cadila healthcare, Evonic Degussa, and Finar chemicals for providing gift sample of Linezolid, Eudragit RS100, Eudragit RL100, Ethyl cellulose, Xanthan gum, Acacia, and Gaur gum, respectively. The author would like to thank Dr. Mukesh. R. Patel for providing necessary facilities REFERENCES
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A traveller presenting with severe melioidosis complicated by a pericardial effusion: a case report

Schultze et al. BMC Infectious Diseases 2012, 12:242http://www.biomedcentral.com/1471-2334/12/242 A traveller presenting with severe melioidosiscomplicated by a pericardial effusion: a casereport Detlev Schultze1*, Brigitt Müller2, Thomas Bruderer1, Günter Dollenmaier1, Julia M Riehm3 and Katia Boggian4 Background: Burkholderia pseudomallei, the etiologic agent of melioidosis, is endemic to tropic regions, mainly inSoutheast Asia and northern Australia. Melioidosis occurs only sporadically in travellers returning fromdisease-endemic areas. Severe clinical disease is seen mostly in patients with alteration of immune status. Inparticular, pericardial effusion occurs in 1-3% of patients with melioidosis, confined to endemic regions. To our bestknowledge, this is the first reported case of melioidosis in a traveller complicated by a hemodynamically significantpericardial effusion without predisposing disease.

Doi:10.1016/j.ejca.2005.06.006

EuropeanJournal ofCancer European Journal of Cancer xxx (2005) xxx–xxx How good are rodent models of carcinogenesis in predicting efficacy in humans? A systematic review and meta-analysis of colon chemoprevention in rats, mice and men Denis E. Corpet *, Fabrice Pierre UMR Xenobiotiques, Institut National Recherche Agronomique, Ecole Nationale Veterinaire Toulouse, BP-87614, 23 Capelles, 31076 Toulouse, France