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FORMULATION AND VALIDATION OF EFFICACY OF NATURAL GUMS AS SOLUBILITY ENHANCERS IN IN-VITRO DISSOLUTION CHARACTERSTICS OF OXCARBAMAZEPINE TABLETS

M. PHARM DISSERTATION PROTOCOL

SUBMITTED TO THE

RAJIV GANDHI UNIVERSITY OF HEALTH

SCIENCES, KARNATAKA, BANGALORE

BY

PATEL MUKESHBHAI ARVINDBHAI B.Pharm

UNDER THE GUIDANCE OF

Dr.R.NAGENDRA RAO

M.Pharm, Ph.D.

PROFESSOR & HEAD

P. G. DEPARTMENT OF QUALITY ASSURANCE

S. C. S. COLLEGE OF PHARMACY,

HARAPANAHALLI-583131

2011-12

Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore

ANNEXURE – II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

|01 |Name and Address of the Candidate |PATEL MUKESHBHAI ARVINDBHAI |

| | |S/O.PATEL ARVINDBHAI BHIKHABHAI |

| | |SATTAR GHAR NI POLE ,NEAR SEVA SAHKARI BHANDAR |

| | |,AT.BHADRAN-388530,DIST.ANAND ,STATE:- GUJARAT |

|02 |Name of the Institution |T. M. A. E. Society’s |

| | |S. C. S. College of Pharmacy, |

| | |Harapanahalli – 583 131 |

| | |(Davangere dist.) Karnataka |

|03 |Course of the Study |M. Pharm., |

| |Branch |Quality Assurance |

|04 |Date of Admission to course |06/07/ 2011 |

|05 |Title of the Topic |FORMULATION AND VALIDATION OF EFFICACY OF NATURAL GUMS AS SOLUBILITY|

| | |ENHANCERS IN IN-VITRO DISSOLUTION CHARACTERSTICS OF |

| | |OXCARBAMAZEPINE TABLETS |

|06 |Brief resume of the intended work | |

| |6.1. Need for the Study |Enclosure – I |

| |6.2. Review of the Literature |Enclosure – II |

| |6.3. Objective of the Study |Enclosure – III |

|07 |Materials and Methods | |

| |7.1. Source of data |Enclosure – IV |

| |7.2. Methods of collection of data |Enclosure – V |

| |7.3. Does the study require any |-No- |

| |Investigations on animals? | |

| |If yes give details | |

| |7.4. Has ethical clearance been |-NOT APPLICABLE- |

| |obtained from your institution In case of 7.3. | |

|08 |List of References |Enclosure – VII |

|09 |Signature of the candidate | |

| | |(PATEL MUKESHBHAI A.) |

|10 |Remarks of the Guide |The present work is aimed at validating the efficacy of natural gums as |

| | |solubility enhancers on solubility characteristics of oxcarbamazepine, |

| | |which may help in improving its solubility and hence its bioavailability.|

|11 |Name and Designation of | |

| |(In Block Letters) | |

| | | |

| |11.1. Guide reference no. of RGUHS |Dr.R.NAGENDRA RAO |

| |ACA/CDC/PGT- |M.Pharm, Ph.D |

| |M.Ph/SCS/02/2005-06/19.01.09 |PROFFESSOR & HEAD |

| | |DEPT. OF QUALITY ASSURANCE, |

| | | |

| |11.2.Signature | |

| | | |

| | | |

| | | |

| |11.3.Co-Guide (if any) | |

| | | |

| | | |

| | | |

| | | |

| |11.4.Signature | |

| | | |

| | | |

| | | |

| |11.5. Head of the Department | |

| | | |

| | | |

| | | |

| | | |

| |11.6.Signature | |

| | | |

| | |Dr.R.NAGENDRA RAO |

| | | |

| | | |

| | |The present work is permitted to carry out in the laboratory of quality |

|12 |Remarks of the Principal |assurance. |

| | | |

| | | |

| |12.1. Signature | |

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| | | |

ENCLOSURE-I

06. Brief resume of Intended Work

6.1 Need for the study.

A convulsion is a medical condition where body muscles contract and relax rapidly and repeatedly, resulting in an uncontrolled shaking of the body. Because a convulsion is often a symptom of an epileptic seizure, the term convulsion is sometimes used as a synonym for seizure. However, not all epileptic seizures lead to convulsions, and not all convulsions are caused by epileptic seizures.

Seizures are episodes of abnormal electrical activity within a network of neurons. Epilepsy means to suffer from repeated seizures that are not provoked by toxins, drugs, infections, or metabolic problems such as low blood sugar. Development of any disease,

Including epilepsy, is influenced by both heredity and environment. One third of the people who develop epilepsy have a minor genetic predisposition to seizures and are then

exposed to a major environmental influence such as brain injury, stroke, meningitis, encephalitis, or brain tumor. However, 70% of people with seizures will develop the disorder because their genetic makeup alone plays a major role, even without an environmental insult1.

Eventhogh these conditions are rarely fatal, these conditions results in debilating effect on persons and have socio-economic effect. Many classes of drugs like anti-convulsants, sedatives, anti-epileptic drugs are used in management of convulstions. Among these classes of drugs, oxcarbamazepine is one of the popularly used anti-convulsant drug.

Oxcarbazepine  is a anticholinergic  anticonvulsant and mood stabilizing drug, used primarily in the treatment of epilepsy. Carbamazepine (CBZ) is used for anticonvulsant and antineuralgic effects. The popularity of this drug is related to several beneficial properties, including proven efficacy in controlling different types of seizures. CBZ is poorly soluble in water with erratic oral absorption and bioavailability less than 70%.It is also used to treat anxiety and mood disorders, and benign motor tics. Oxcarbazepine is a structural derivative of Carbamazepine. Oxcarbazepine that is 10, 11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide is a 10-keto analog of Carbamazepine Oxcarbazepine is a poorly water-soluble, anti-epileptic drug according to the BCS system (Class II), and its dissolution is the rate-limiting step for absorption . Drug absorption from solid dosage forms after oral administration depends on the release of the drug substance from the drug product, the dissolution or solubilization of the drug under physiological conditions, and the permeability across the gastrointestinal tract.

Many attempts are made in past in which CBZ has been converted into various novel drug delivery forms to overcome the solubility problem like preparation of its solid dispersions, nanoparticles, microspheres, neosome etc. Novel approaches where natural polymers like gum karaya, modified gum karaya, guar gum and other natural gums for preparations of solid dispersions are being widely investigated.

Process validation is an integral part development of novel formulations. Process validation is the means of ensuring and providing documentary evidence that processes (within their specified design parameters) are capable of consistently producing a finished product of the required quality. Process validation is carried out in every step of development of novel formulation to ensure the quality of finished product. In the present work also, the concept of process validation will be utilized for selecting an ideal formulation.

In the present work, similar attempt will be made by for formulation of CBZ with various natural and modified natural polymers and further they will be converted into tablets. Thus prepared tablets will be validated by using various physicochemical parameters in hope of getting a suitable formulation which is devoid of solubility problem and enhanced bioavailability.

ENCLOSURE-II

6.2 Review of Literature

CBZ is one of the most widely used anti-convulsant drug. CBZ comes under the class-2 of the BCS classification so it possesses low solubility. There are many literature reports available in which various natural (simple and modified) gums are used for the purpose of increasing the solubility of low soluble drugs. Some of them are mentioned below. Many attempts are also done to improve the solubility of CBZ by various methods.

1. The aims of this study were (1) to compare the in vitro dissolution profiles of Oxcarbazepine-HP b-CD tablet formulations with those of marketed Oxcarbazepine tablets, (2) to apply statistical models to evaluate each method in terms of easy application and usefulness, and (3) to identify the advantages and disadvantages of each method. The results show that the tablets containing hydroxypropyl b-cyclodextrin (HP b-CD) with sodium carboxymethylcellulose (NaCMC) exhibit faster release (1.93-fold) than marketed Oxcarbazepine (OXO) tablets. From Weibull parameters, it was shown that Td is three times higher for OXC-HP b-CD with NaCMC tablets than for marketed Oxcarbazepine tablets. The release kinetics of OXC complexed with HP b-CD from different tablets was investigated using several mathematical equations. Model-independent methods including difference factor, f1, and similarity factor, f2; model-dependent methods; and ANOVA-based methods were used for the comparison of in vitro dissolution profiles. The results show that ANOVA-based methods and model-dependent methods are more discriminative than model-independent methods. Model independent methods seem to be easier to apply and interpret; only one value is obtained to describe the closeness of the two dissolution profiles. 2

2. Nirav Patel et al.,worked on Comparison of In Vitro Dissolution Profiles of Oxcarbazepine-HP b-CD Tablet Formulations with Marketed Oxcarbazepine Tablets. Oxcarbazepine is an anticonvulsant drug, mainly used as an add-on or first line treatment in adults and children. Due to sudden onset of attack, it is necessary to formulate antiepileptic into such a delivery system, which provide immediate relief. Hence, the present investigation was undertaken with a view to develop mouth-dissolving tablets of Oxcarbazepine, which offers a new range of product having desired characteristics and intended benefits. In this study, the mouth dissolving tablets were prepared using two different technologies, direct compression method and solid dispersion technology. Tablets produced by direct compression method contain crospovidone as a super disintegrant and aspartame as a sweetener. Solid dispersions of Oxcarbazepine with polyvinylpyrrolidone K-30 and polyethylene glycol 6000 in different weight ratios were prepared with a view to increase its water solubility. Oxcarbazepine solid dispersions with Polyvinylpyrrolidone K-30 in 1:2 ratios of drug: carrier showed maximum drug release and hence, compressed along with other excipients into mouth dissolving tablet. The results compared for both the technologies showed that the Oxcarbazepine tablets prepared using solid dispersion technology was found to have good technological properties and satisfying and reproducible drug dissolution profiles. Moreover the drug release was found to be comparable to the marketed dispersible tablet3.

3. Anupama Kalia et al., studied on formulation and evaluation of mouth dissolving tablets of Oxcarbazepine, The objective of this work was to develop tablet formulations of Oxcarbazepine-beta-cyclodextrin (OX-beta-CD) binary systems. Three types of binary systems--physical mixtures, kneaded systems, and co evaporated systems--were studied. Phase solubility studies indicated 1:1 M complexation of Oxcarbazepine with beta-cyclodextrin. Drug-beta-CD binary systems were prepared at 1:1 molar ratios and used in formulation studies. The dissolution properties of OX-beta-CD KS (kneaded system, 100.10% drug release in 15 min) were superior than those of the other binary system and pure Oxcarbazepine. The tablet formulations containing drug-beta-CD binary systems prepared by wet granulation and direct compression showed superior dissolution properties when compared with the formulations of the corresponding pure drug formulations. Tablet formulations containing drug-beta-CD binary systems prepared by the kneading method showed good dissolution properties (100% drug release in 15 min in direct compression method and 99.9% drug release in 20 min in wet granulation method). Overall, the dissolution properties of tablet formulations prepared by the direct compression method were superior to those of tablets prepared by the wet granulation method. Accelerated stability studies on some selected tablet formulations were also conducted by keeping the samples at 40 +/- 2 degrees C and 75% relative humidity. There were no statistical differences in the percentage of drug dissolved at 15 and 20 min between fresh and stored samples at the different time points (P < 0.05). Drug content also remained within acceptable limits. Thus, drug-beta-CD binary systems are useful in developing tablet formulations of Oxcarbazepine with improved dissolution properties4.

4. Patel NV et al., carried out research on tablet formulation studies on an Oxcarbazepine-beta cyclodextrin binary system The purpose of this study was to fabricate the polyethylene glycol matrix tablet by mold technique. Indomethacin and hydroxypropylmethylcellulose were used as model drug and polymer, respectively, in PEG matrix system. The physical and drug release characteristics of developed matrix tablet were studied. This inert carrier system comprising 7:3 polyethylene glycol 4000: polyethylene glycol 400 could effectively enhance the solubility of indomethacin and an addition of Hydroxypropylmethylcellulose could sustain the drug release. Scanning electron microscope photomicrograph indicated the drug diffusion outward through the porous network of this developed matrix tablet into the dissolution fluid. Least square fitting the experimental dissolution data to the mathematical expressions (power law, first-order, Higuchi's and zero-order) indicated the drug release kinetics primarily as Fickian diffusion. Both the enhancement of drug dissolution and the prolongation of the drug release could be achieved for aqueous insoluble drug such as, indomethacin, by using polyethylene glycol-hydroxypropylmethylcellulose matrix system prepared with melting and mold technique.5

5. Mesnukul A et al., carried out research work on Solid dispersion matrix tablet comprising Indomethacin-PEG-HPMC fabricated with fusion and mold technique, , Solid dispersion matrix tablet comprising Indomethacin-PEG-HPMC fabricated with fusion and mold technique, Cefixime is an oral third generation cephalosporin antibiotic used in the treatment of gonorrhea and tonsillitis, which has oral bioavailability of 40-50% and it belongs to the BCS class-II. Many attempts are made in the past to increase its solubility by preparing its solid dispersions. However, very few literature reports are available wherein natural polymers are used for preparation of solid dispersions. In the present work, an attempt is made to increase the solubility of Cefixime by preparing its solid dispersions using natural polymer i.e.., guar gum. Various techniques used for preparing Solid dispersions are by Physical mixture, Kneading and Solvent evaporation methods using different drug-polymer ratio. Thus prepared solid dispersions were evaluated for percentage yield, drug content, saturation solubility and in-vitro dissolution studies. The result obtained from above studies indicated that, the solubility and dissolution of Cefixime solid dispersions was improved as compared to pure drug by all the methods employed. Among various methods employed, solvent evaporation method produced good results compared to Physical mixture, Kneading method. Hence, Solid dispersion technology can be used to improve the solubility of Cefixime6.

6. Suchetha Reddy Aleti et al., studied solubility and dissolution enhancement of cefixime using natural polymer by solid dispersion technique Present study examines the effect of Guar gum (GG) and Modified guar gum (MGG) on the solubility of a poorly water-soluble class II drug licofelone. Modified guar gum (MGG) was prepared using heat treatment (125-130oC for 2 to 3 hours) method. It was characterized for viscosity, swelling index and water retention capacity. The physical and co-grinding mixtures of licofelone with GG and MGG were prepared in 1:6 drug to gum ratio. The physical and co-grinding mixtures were characterized by DSC and FT-IR study. The studies confirmed that there was no interaction between drug and carrier. Prepared mixtures were evaluated for solubility study and in vitro dissolution studies using USP XXIII Dissolution apparatus. The results of present investigation indicated that co-grinding mixture of licofelone with modified guar gum could be useful in developing an oral dosage form with increased solubility and hence improved dissolution and oral bioavailability of poorly water Soluble drug.7

7. Vandana B. Patel et al., carried out research on studies in Prospective Process Validation of Cimetidine Tablet Dosage Form The purpose of the research investigation was to study prospective process validation of Cimtidine 400 mg tablet dosage form. Quality cannot be adequately assured by in-process and finished inspections and testing but it should be built in to the manufacturing process. The critical process parameters were identified with the help of process capability and evaluated by challenging its lower and upper release specifications. Three initial process validation batches of same size, method, equipment & validation criteria were taken. The critical parameter involved in sifting, dry mixing, preparation of granulating agent, wet mixing, wet milling, drying, sizing, lubrication & compression stages were identified and evaluated as per validation plan. Film coating of tablet were evaluated for coating uniformity, coating process efficiency and surface roughness. The spry rate , atomization air pressure, distance of nozzle from tablet bed, inlet air temperature, pan differential pressure ,pan speed and % solid content these affect the final film quality of coated tablets.8

8. M. A. Satish et al., worked on spectrophotometric determination of oxcarbazepine in pharmaceutical formulations. A simple, rapid, economical and highly sensitive spectrophotometric method is developed for determination of oxcarbazepine (OXC) in pure and in pharmaceutical formulations. The method is based on reaction of OXC with methanolic potassium hydroxide in dimethyl sulfoxide (DMSO) medium to form a colored product, which shows maximum absorption at 430nm. The conditions necessary for the assaying the drug are established. The system is obeying the Beer’s law over its concentration range of 1.0‐7.02 μgml‐1. The calculated molar absorptivity and sandell’s sensitivity values are 1.21X104 l mol‐1cm‐1 and 0.0208μg/cm2 respectively. The limit of detection (LOD) and limit of quantification (LOQ) of the proposed method are found to be 0.027 and 0.082 μg/ml respectively. The method does not suffer any interference from common tablets excipients up to 40mg. Themethod is found to be successful for the determination of OXC either in its pure form or in pharmaceutical formulations with good accuracy and precision.9

9) Sravani Shilpa.K et al., worked on formulation and Process Validation of Clopidogrel Bisulfate 300mg Tablet .The purpose of the study of process validation is to create a robust formulation and to validate all the critical parameters challenge in manufacturing process like drying, blending,compression lubrication, coating and packaging ,finally by seeing the results we can say that the process validation follow twas correct and are as per the Cgmp requirements. 10

10) Pravin Pandharmise et al., studied in prospective Process Validation of Gliclazide Tablet 80 mg Dosage Formulation. The purpose of research was to study prospective process validation of Gliclazide Tablet 80 mg after successful completion of the Optimization batch of solid dosage formulation. The critical process parameter was identified with the help of optimization batch(s) of process capability and evaluated by challenging specification. Three process validation batches (1009G0519, 1009G0520 & 1009G0521) of same size, manufacturing process, equipment &validation criteria was taken. The critical parameter involved in sifting, dry mixing, preparation of granulating agent, wet mixing, wet milling, drying, sizing, lubrication & compression stages were identified and evaluated.11

ENCLOSURE -III

6.3 Objectives of the study:

In the present work, by using suitable literature methods and physical mixture of CBZ with various natural gums (both simple and modified) will be prepared. Thus prepared mixture will be analyzed by suitable analytical techniques to study any possible interaction between drug and polymers. Pharmacokinetic properties of prepared physical mixture will be evaluated by using various parameters. The steps which are intended to be carried out are as follows.

Step-1: Selection of various natural gums and modification of natural gums for preparation of physical mixture of CBZ.

Step-2: Preparation of Physical mixture of CBZ with selected gums.

Step-3: Study of interaction of gums with polymers.

Step-3: Validation of preparation methods by employing suitable formulation and process variable.

Step-5: Formulation of physical mixture into tablets using suitable excipients.

Step-6: Validation of prepared formulation by using various physicochemical

Parameters.

ENCLOSURE – IV

7. Material & methods:

7.1 Source of data:

1. The primary data required for designing the work will be collected from Various national and international journals available in college library.

2. From various open access journals available in internet, from helinet service of RGUHS, Bangalore, From various reference books available in college library, from various search engines like , etc.,by referring various journals from libraries of Indian Institute of Science, Bangalore, Libraries of various Universities liker Kuvempu University, Shankargatta, Karnataka University, Dharwad.

3. The targeted drug Carbamazepine ( CBZ) will be first tested for purity using standard procedures.

4. Various natural gums like xanthan gum, gum karaya etc will selected for the preparation of solid dispersions.

5. To study the possibility of interaction of CBZ with the gums used, various analytical analysis like IR, DSC will be carried out and data collected from the data will be used for selecting suitable polymers.

6. Various formulations of solid dispersion containing CBS and gums will be prepared and an evaluated for % drug loading, % encapsulation efficiency, particle size distribution, in-vitro dissolution studies, etc.

7. For validation of formulations, the best formulation will be selected and the polymers used in the selected formulation will be validated by

A. Further changing the concentration of polymer

B. By changing the preparation conditions

8. Thus prepared formulations will evaluated and various data collected from evaluation of prepared formulations like % drug loading, % encapsulation efficiency, particle size distribution, in-vitro dissolution studies, etc., will be used for selected the optimum concentration of polymer and conditions for preparation of formulation.

ENCLOSURE – V

7.2 Method of collection of data:

1. By using suitable methods, physical mixture of CBZ and Simple and modified

natural gums will be prepared.

2. Characterization of physical mixture by various analytical techniques like IR

DSC, etc.

3. Based on data obtained from analytical methods, if required validation of the

Preparation method employed for preparing physical mixture will be carried

Out.

4. Thus prepared physical mixture will be formulated into table Using various suitable excipients..

5. Thus prepared formulations will be validated to find a suitable formulation by evaluating

a. Percentage drug loading by Ultraviolet spectroscopy.

b. Percentage encapsulation efficiency by Ultraviolet spectroscopy.

c. Compatibility studies between various ingredients by using DSC, IR.

d. In-vitro dissolution and diffusion study by USP method.

6. Validation for identification of a suitable formulation using the data obtained from the above methods (Step-5).

ENCLOSURE – VI

8.0 List of references:

1) Book of Genes, Seizures & Epilepsy by Alica M.and Goldman, M.D., Ph.D. EP Magazine; September 2006 ; 52-59

2) Nirav Patel, Narendra Chotai, Jayvadan Patel, Tejal Soni, Julan Desai and Rajnikant Patel, Comparison of In Vitro Dissolution Profiles of Oxcarbazepine-HP b-CD Tablet Formulations with Marketed Oxcarbazepine Tablets , Dissolution Technologies , 2008;28-34.

3) Anupama Kalia, Shelly Khurana and Neena Bedi, Formulation and evaluation of mouth dissolving tablets of Oxcarbazepine, International journal of pharmacy and pharmaceutical sciences,2009; 1(1): 12-23.

4) Patel NV, Chotai NP and Patel MP, Tablet formulation studies on an Oxcarbazepine-beta cyclodextrin binary system, Pharmazie. 2008; 63(4):275-81.

5) Mesnukul A, Yodkhum K and Phaechamud T, Solid dispersion matrix tablet comprising Indomethacin-PEG-HPMC fabricated with fusion and mold technique, Indian journal of pharmaceutical sciences, 2009; 71(4) : 413-420.

6) Suchetha Reddy Aleti, Rangaraju D, Aman Kant, Shankraiah MM, Venkatesh JS. Nagendra Rao R and Nagesh C, Solubility and Dissolution enhancement of cefixime using natural polymer by solid dispersion technique , International journal of Research in pharmacy and chemistry, 2011;1(2): 2231-2781.

7) Shah Viral, Patel Dhiren,Sandeep Mane and Upadhyay Umesh, Solubility and Dissolution Rate Enhancement of Licofelone by Using Modified Guar Gum, International Journal of PharmTech Research,2010; 2(3):1847-1854.

8) Vandana B. Patel , Minaxi R. Rathwa and Kandarp Patel, Studies in Prospective Process Validation of Cimetidine Tablet Dosage Form. International Journal of Research in Pharmaceutical and Biomedical Sciences.2011;2(4).

9) M. A. Satish and G. Nagendrappa, Spectrophotometric determination of oxcarbazepine in pharmaceutical formulations. International Journal of Pharmacy and Pharmaceutical Sciences .2010;l 2(3)

10) Sravani Shilpa.K1*, Meka Anand Kumar, Senthil Kumar.M Formulation and Process Validation of Clopidogrel Bisulfate 300mg Tablet. International Journal of Pharmaceutical Quality Assurance.2011;3(4)

11) Pravin Pandharmise, Abhijit Kulkarni, Shahzad Naiyar, Deepak Sharma, Anil Kamble Studies in Prospective Process Validation of Gliclazide Tablet 80 mg Dosage Formulation. International Journal of PharmTech Research.2011;3(3):1515-1520.

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