APPLICATION OF SOLID DISPERSION TECHNIQUE IN THE FORMULATION OF CARBAMAZEPINE DISPERSIBLE TABLETS TO ENHANCE SOLUBILITY

Synopsis for M.Pharm Dissertation submitted to the
Rajiv Gandhi University of Health Sciences, Bengaluru, Karnataka.
By

Mr. P. HARI KRISHNA YADAV

M.Pharm., Part-I

Under the guidance of

Dr. GANESH N.S.,M.Pharm.,Ph.D.,

ASSOCIATE PROFESSOR

DEPARTMENT OF PHARMACEUTICS

SARADA VILAS COLLEGE OF PHARMACY

KRISHNAMURTHYPURAM

MYSORE- 570004

2011-2012

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

KARNATAKA, BENGALURU.

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / NAME OF THE CANDIDATE
AND ADDRESS (IN BLOCK LETTERS) / P. HARI KRISHNA YADAV
M. PHARM., PART –I
DEPARTMENT OF PHARMACEUTICS,
SARADAVILAS COLLEGE OF PHARMACY,
KRISHNAMURTHYPURAM, MYSORE-04
2. /

NAME OF THE INSTITUTION

/ SARADAVILASCOLLEGE OF PHARMACY,
MYSORE.
3. /

COURSE OF STUDY AND SUBJECT

/ MASTER OF PHARMACY IN PHARMACEUTICS.
4. / DATE OF ADMISSION OF COURSE / 15-12-2011
5. / TITLE OF TOPIC / APPLICATION OF SOLID DISPERSION TECHNIQUE IN THE FORMULATION OF CARBAMAZEPINE DISPERSIBLE TABLETS TO ENHANCE SOLUBILITY
6. / BRIEF RESUME OF THE
INTENDED WORK
6.1 Need for the study
6.2 Review of the literature
6.3 Objectives of the study / ENCLOSURE - I
ENCLOSURE - II
ENCLOSURE – III
7. /

MATERIALS AND METHODS

7.1 Source of data

7.2 Method of collection of data

7.3Does studies require any investigations or interventions to be conducted on patients or other human or animal? If so, please describe briefly.

7.4 Has ethical clearance been obtainedfrom your institution in case of 7.3

/ ENCLOSURE – IV
ENCLOSURE - V
ENCLOSURE – VI
ENCLOSURE – VI
8. / LIST OF REFERENCES / ENCLOSURE – VII
9. / SIGNATURE OF CANDIDATE
10. / REMARKS OF GUIDE / RECOMMENDED
11. / NAME AND DESIGNATION OF
11.1 Guide
11.2 Signature
11.3 Head of department
11.4 Signature / Dr. GANESH N.S,M.Pharm., Ph.D.,
ASSOCIATE PROFESSOR,
DEPARTMENT OF PHARMACEUTICS,
SARADAVILASCOLLEGE OF PHARMACY,
KRISHNAMURTHYPURAM, MYSORE -04
Dr.C. JAYANTHI,M.Pharm., Ph.D.,
PROFESSOR AND HEAD,
DEPARTMENT OF PHARMACEUTICS,
SARADAVILASCOLLEGE OF PHARMACY,
KRISHNAMURTHYPURAM, MYSORE -04
12. / 12.1 Remarks of the Principal
12.2 Name and designation of principal
12.3 Signature / RECOMMENDED & FORWARDED
Dr.K.HANUMANTHACHAR JOSHI,
M.Pharm., Ph.D.,
PRINCIPAL,
SARADAVILASCOLLEGE OF PHARMACY,
KRISHNAMURTHYPURAM, MYSORE- 04
6.0
7.0
8.0 / BRIEF RESUME OF THE INTENDED WORK
ENCLOSURE-I
6.1 Need for the study
Due to its convenience and ease of administration oral route is preferred for delivery of most of the drugs. Greater stability, easy production, accurate dosage and patient’s perspective is the main reason behind the preference of solid oral dosage form. It is well established that the active ingredient in a solid oral dosage form must undergo dissolution before it is available for absorption from the GIT. Both the permeability and solubility behavior of a drug are the major determinants of its oral bioavailability. Poor solubility behavior of a drug is the major determinants of its oral bioavailability. Poor solubility of a drug results in reduced bioavailability increases in the dosage, large variation in drug blood concentration and large variation in drug blood concentration and large inter and intra subject variability1.
Solid dispersion is generally prepared with drug which is having poor aqueous solubility and hydrophilic carrier. In solid dispersion particle size of drug is reduced or a crystalline pure drug is converted into amorphous form and hence the solubility of drug is increased. Solid dispersion is not only used in improving dissolution rate of poorly water soluble drug but also in masking the taste of the drug substance, preparing rapid disintegration oral tablets and in producing sustained release microspheres. Solid dispersion has traditionally been defined as the “the dispersion of one or more active ingredients in an inert excipient or matrix” where the active ingredients could exist in finely crystalline, solubilized or amorphous states. It is the most promising method to formulators because of ease of preparation, ease of optimization and reproducibility2.
Carbamazepine is a dibenzazepine derivative with antiepilepticand psychotropic properties. It is also used in the treatment of trigeminal neuralgia and pain associatedwith other neurological disorders It belongs to Class II biopharmaceutical classification system (BCS) which is characterized by high membrane permeability, slow dissolution rate due to low aqueous solubility, and high per oral dose Carbamazepine is a widely prescribed antiepileptic drug having poor water solubility (170mg/l at 250 C). Because of having poor water solubility,its absorption is dissolution rate limited, which often results in irregular anddelayed absorption3, 4.
In the present study solid dispersion of carbamazepine is to be formulated as dispersible tablets in order to enhance its solubility. Dispersible tablets are uncoated or film-coated tablets intended to be dispersed in water before administration giving a homogeneous dispersion. Oral dosage forms like tablets and capsules possess great problem of swallowing mainly for pediatric and geriatric patients and nauseous or non-compliant patients too.
ENCLOSURE – II
6.2 Review of the literature
  1. Setia A. et al., studied on formulation and evaluation of ciprofloxacin hydrochloride dispersible tablets using natural substances as disintegrants. Dispersible tablets of ciprofloxacin hydrochloride were prepared using natural substance as disintegrants such as Isabgol husk powder, alginic acid and agar powder in different concentrations by direct compression method. Dispersible tablets of ciprofloxacin hydrochloride were prepared using direct compression method after incorporating different natural disintegrates. It was observed that all the formulations were acceptable with reasonable limits of standard required for dispersible tablets. This study reveals that natural gums used as disintegrants were effective and isabgol at a concentration of 5% produce best dispersible effects5.
  2. P.V.Swamy et al., Designed orodispersible tablets of meloxicam using combination of super-disintegrants i.e., sodium starch glycolate – croscarmellose sodium or sodium starch glycolate – crospovidone. Among the two formulations, the formulation prepared by direct compression method using 2% w/w sodium starch glycolate and1.5% w/w croscarmellose sodium was found to be a better formulation6.
  3. Jadhav SB. et al., carried out formulation and evaluation of dispersible tablets of diltiazem hydrochloride. Dispersible tablets prepared using superdisintigrants such as croscarmellos sodium (Ac-Di-Sol) and sodium starch glycolate. Formulations were evaluated for the standard of dispersible tablets. It was observed that all the formulations were in an acceptable range with reasonable limits of standards required for dispersible tablets. The study reveals that superdisintigrants used were effective in low concentrations. It was concluded that dispersible tablets with enhanced dissolution rate can be made using selected superdisintegrants7.
  4. Jain.C. P and Naruka. P. S et al., prepared fast dissolving tablets of valsartan using different superdisintegrants by direct compression method, evaluated the tablets for physicochemical properties and in vitro dissolution. Effect of disintegrants on disintegration behavior of tablet in artificial saliva, pH 5.8 was evaluated. Wetting time of formulations containing Crospovidone was least and tablets showed fastest disintegration. The drug release from FDTs increased with increasing concentration of superdisintegrants and was found to be highest with formulations containing Crospovidone. The release of valsartan from FDTs was found to follow non-Fickian diffusion kinetics8.
  5. S B Shirsand et al., prepared fast dissolving tablets of clonazepam by direct compression method. Three super-disintegrants, viz., crospovidone, croscarmellose sodium and sodium starch glycolate in different ratios with microcrystalline cellulose along with directly compressible mannitol used to enhance mouth feel. The prepared batches of tablets were evaluated for hardness, friability, drug content uniformity, wetting time, water Absorption ratio andin vitrodispersion time. Based onin vitrodispersion time, three formulations were tested for thein vitrodrug release pattern, short-term stability and drug-excipients interaction. Among the formulations, the formulation prepared by using 10% w/w of crospovidone and 35% w/w of microcrystalline cellulose emerged as the overall best formulation9.
  6. Mahadevappa V. Rampure et al., prepared fast dissolving phenobarbitone tablets by direct compression method with a view to enhance patient compliance. The methodology worked out was by using three superdisintegrants (2-8%w/w) i.e., L-hydroxypropyl cellulose, pregelatinized starch, crospovidone with varying concentration of microcrystalline cellulose(5-15%w/w) and directly compressible mannitol was used as a diluent to enhance the mouth feel. The prepared batches of tablets were evaluated for post compression parameters. Three promising formulations were tested for drug release pattern in pH 6.8 phosphate buffer. Among the promising formulations, the formulations containing 8% w/w of crosspovidone and 15% w/w of microcrystalline cellulose emerged as the overall best formulation10.
  7. Kuchekar BS. et al., carried out formulation and evaluation of norfloxacin dispersible tablets using natural substances as disintegrants. Dispersable tablets of norfloxacin were prepared using natural substances as disintegrants such as ispaghula husk powder, cassia tora powder, cassia tora powder (defatted) and cassia nodosa powder in different concentrations by direct compression method. Prepared formulations were compared with marketed products. It was observed that all that formulations were within acceptable limits of standards required for dispersible tablets. The study revealed that natural gums used as disintegrates were effective in low concentration11.
  8. Patel DM et al., formulated orodispersible tablets of Rofecoxib by granulation method that carried out by solid deposition method using threesuperdisintegrants namely SSG, crospovidone and croscarmellose sodium. From that crospovidone giving lowest disintegration time and wetting time as compared to remains superdisintegrants12.
  9. RangasamyM et al., fast dissolving tablets of terbutalinesulfate were prepared by the direct compression method after incorporating supredisintegrants such as Explotab, Ac-Di-Sol and polyplasdone XL in different concentrations. The prepared tablets were evaluated for weight variation, thickness, hardness, friability, wetting time, drug content, water absorption ratio, in vitro dispersion time, in vitro disintegration time and in vitro drug release. Among all, the formulation F9 (containing 5%w/w concentration of polyplasdone XL) was the best formulation, which releases up to 99.33% of the drug in 10 min13.
  10. Gohel Mprepa et al., prepared the mouth dissolved tablets of Nimesulide using vacuum drying technique. Granules containing Nimesulide, camphor, crospovidone and lactose were prepared by wet granulation technique. Camphor was sublimed from the dried granules by exposure to vacuum. The tablets were evaluated for % friability, wetting time and disintegration time14.
  11. Areefulla HS et al., have designed orodispersible tablet of Itopride Hydrochloride were designed with a view to enhance patient compliance by sublimation method with using Crospovidone (2-10%) as super-disintegrant along with directly compressible Mannitol to enhance mouth feel. The prepared formulations were evaluated for hardness, friability, drug content uniformity, wetting time and in vitro dispersion time. From their study they concluded that formulation prepared by sublimation method, emerged as the overall best formulation (t25%=2.9min) compared to the commercial formulation (t50%>30min) i.e., it shows 10 times faster drug release in pH 6.8 phosphate buffer15.
  12. Yadav R et al., worked on formulation and in vitro evaluation of Orodispersible dosage form of Stavudine, prepared by direct compression method. They use sugar and superdisintegrants i.e. crosscarmellose calcium, sodium starch glycolate and Crospovidone. The tablet where evaluated for drug content, content uniformity, weight variation, hardness, friability, water absorption ratio, in-vitro disintegration time and in-vitro dissolution study. From their study they concluded that orodispersible dosage form is an alternative to conventional tablets showing enhanced dissolution and hence better patient compliance and effective therapy16.
ENCLOSURE-III
6.3 Objectives of the study
The specific objective of the study is:
  1. To increase the solubility of poorly soluble drug Carbamazepine.
  2. To prepare solid dispersion of Carbamazepine
  3. To formulate dispersible tablets of Carbamazepine solid dispersion.
  4. To carry out the preformulation and postformulaton parameters of prepared dispersible tablets.
  5. The in vitrorelease data fit into various kinetic models.viz. First order, Second order,Higuchi, Peppa’setc.,
  6. To characterize the formulation by instrumental methods like FTIR, DSC and PXRD.
MATERIALS AND METHODS
Materials:
  • API: Carbamazepine.
  • Superdisintegrants: Crospovidone,Croscormellose, Sodium starch glycolate.
  • Diluents: Micro crystalline cellulose, lactose, etc.
  • Sweetening agent: Aspartame, Sodium saccharine, Sucrose.
  • Subliming agent: camphor, menthol, thymol, ammonium bicarbonate.
  • Carriers: PEG6000, urea, mannitol.
  • Other excipients: Magnesium stearate, talc, etc.
Methods:
  • Solid dispersion of carbamazepine formulation was prepared by Melt fusion method, Solvent evoparation method, Co precipitation.
  • Solid dispersion of carbamazepine was punched into dispersible tablets by Direct compression method by using superdisintegratnts and additives.
Evaluation:
Pre compression parameters:
  • Drug-polymer interaction
  • Angle of repose
  • Bulk density
  • Tapped density
  • Carr’s compressibility index
  • Hausner’s ratio
Post compression parameters:
  • Weight variation
  • Hardness
  • Friability
  • Drug content estimation
  • In vitro disintegration time
  • Wetting time
  • In vitro dispersion time
  • In vitro dissolution studies
  • In vitroRelease kinetics
ENCLOSURE-IV
7.1. Source Of Data
The preliminary data required for the experimental study was obtained from:
  • Library: Sarada Vilas College of Pharmacy
  • E-Library: Sarada Vilas College of Pharmacy
  • Research publications
  • Official monographs
ENCLOSURE-V
7.2. Method of collection of data
Data on drug would be collected by performing laboratory experiments as per the methods and techniques as mentioned above (Materials and Methods)
ENCLOSURE-VI
7.3 Does the study require any investigations or interventions to be conducted on patients or other humans or animals? If so, please describe briefly.
-Not applicable-
7.4 Has ethical clearance been obtained from your institute in case of 7.3?
-Not applicable-
ENCLOSURE-VII
LIST OF REFERENCES:
  1. Rinaki E., Valsami, G., and Macheras, P. Quantitative Biopharmaceutics classification system: S e central role of dose/solubility ratio. Pharm Res2003; 20: 1917–25
  2. Lobenberg R, Amidon GL. Modern bioavailability, bioequivalence and Biopharmaceutics classification system: new scientific approaches to international regulatory standards. Eur. J. Pharm. Bio pharm 2005; 50: 3-12.
  3. Teofilo Vasconcelos, Bruno Sarmento and Paulo Costa. Solid dispersions as strategy to improveoral bioavailability of poor water soluble drugs.Drug Discovery Today 2007; 12: 1068-75.
  4. Verheyen S, Blaton N, Kinget R, Mooter VD. Mechanism of Increased Dissolution ofDiazepam and Temazepam from Polyethylene Glycol 6000 Solid Dispersions. I J Pharm2002; 249: 45-58.
  5. Setia A, Goyal N, Kansal S. Formulation and evaluation of Ciprofloxacin hydrochloride dispersible tablets using natural substances as disintegrates. Der Pharmacia Sinica2011;2(1):36-39.
  6. P.V.Swamy, S.H.Areefula, S.B. Shrisand, SmithaGandra and B. Prasanth. Orodispersible tablets of meloxicam using disintegrate blends for improved efficacy. Indian Journal of Pharmaceutical Sciences 2007; 11: 836 – 39.
  7. Jadhav SB, Kaudewar DR, Kaminiwar GS, Jadhav AB, Kshirsagar RV, Sakarkar DM. Formulation and Evaluation of Dispersible Tablets of Diltiazem Hydrochloride. Int J Pharm Tech Res 2011;3(3):1314-21.
  8. Jain.C. P, Naruka. P. Formulation and Evaluation of Fast Dissolving Tablets ofValsartan”. Indian Journal Pharmacy and pharmaceutical sciences 2009; 1(1): 220-26.
  9. SBShirsand, Sarasija Suresh, PV Swamy, D Nagendra Kumar, MV Rampure. Design and evaluation of fast dissolving tablets of clonazepam. Indian Journal of pharmaceutical sciences 2008;70(6): 791-95.
  10. Mahadevappa V. Rampure, BasawarajBendegumble. S.AppalaRaju, RaghunandanD. And P.V. Swamy. Formulation Design of Rapidly Disintegrating Phenobarbitone Tablets by Direct Compression Method. International Journal of Pharma and Bio Sciences 2010; 1(4): 62-68.
  11. Kuchekar BS, Pattan SR, Godge RK, Laware RB, Nirmal SA, Parjane SK et al., Formulation and Evaluation of Norfloxacin Dispersible Tablets using Natural substance as Disintegrants. Journal of Chemical and Pharmaceutical Research 2009;1(1):336-41.
  12. Patel DM, Patel MN, Shah RR, Jogani PD. Formulation of orodispersiblerofecoxib tablets. Indian J Pharm Sci 2004; 66(5):621-25.
  13. Rangasamy M, Ayyasamy B. Design and evaluation of the fast dissolving tablet of terbutalinesulfate. Asian J Pharm 2009; 215-17.
  14. Gohel M, Patel M, Amin A, Agrwal R, Dave R, Bariya, N. Formulation design and optimization of mouth dissolve tablets of nimesulide using vacuum drying technique. AAPS Pharm Sci Tech 2004; 5(3):1-6.
  15. Areefulla HS, Mujaheed A, Raheem MA, Ayesha S, Bilguese F et al. Orodissolving tablets of Itopride Hydrochloride prepared by sublimation technique. Indian J Pharm sci 2009; 71(2):168.
  16. Yadav R, Gupta RN, Yadav C. Formulation and In-Vitro evaluation of Orodispersible Dosage form of Stavudine. Indian J Pharmsci 2009; 71(2): 163-64.