WHO Drug Information Vol. 1, 2016 2 Pre-publication draft - page numbers are not for citation purposes 72 Misoprostol dispersion 76 Misoprostol tablets 79 Carbamazepine 84 Carbamazepine tablets 87 Carbamazepine chewable tablets 90 Carbamazepine oral suspension International Nonproprietary Names (INN) 93 Recommended INN: List 75 Continued. We evaluated 263 approved generic drugs of IR products listed on the WHO EML to find out the distribution of BCS Class 1, 2, 3, and 4 drugs in approved ANDA applications during the 2000 to 2011 period. The WHO EML was used as it is a publicly available list of Class 1, 2, 3, and 4 drugs. A drug product is eligible for a BCS-based biowaiver provid that the drug substance(s) satisfy the ed criteria regarding solubility and permeability (BCS Class I and III), the drug product is an immediate-release oral dosage form with systemic action, and the drug product is dosage the same form and strength as the reference product. Nevertheless, several Class IV drugs do exist (7, 9, 10). Examples include hydrochlorothiazide, taxol, and furosemide. BCS CLASS BOUNDARIES Class boundary parameters (i.e., solubility, permeability, and dissolution) are for easy identification and determination of BCS class (2, 4 11). Solubility: A drug substance is considered highly soluble.

SOLUBILITY ENHANCEMENT OF BCS CLASS II DRUG USING LYOPHILISATION TECHNIQUE AND DETERMINATION OF BIOAVAILABILITY IN ANIMALS USING CATALEPSY MODEL

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SOLUBILITY ENHANCEMENT OF BCS CLASS II DRUG USING LYOPHILISATION TECHNIQUE AND DETERMINATION OF BIOAVAILABILITY IN ANIMALS USING CATALEPSY MODEL

M. P. Ratnaparkhi ^*1 and P. D. Chaudhari ²

Marathwada Mitra Mandal’s College of Pharmacy ¹, Thergaon (Kalewadi), Pune - 411033, Maharashtra, India.

PES Modern College of Pharmacy ², Nigdi, Pune - 411044, Maharashtra, India.

ABSTRACT: Ziprasidone HCl is a newly introduced atypical antipsychotic drug. It has its own unique multi receptor binding affinity. This makes it a unique special choice of antipsychotic agent. It mainly acts as antagonist of D₂ dopamine receptors as and 5HT₂A (serotonin, 5HT, 5-hydroxytryptamine) receptors. It is pinkish brown colored powder having very low solubility in water (21.12 mg/L). The main purpose of this study is to enhance the solubility of Ziprasidone HCl using lyophilisation technique. The β-Cyclodextrine and Hydroxy Propyl- β-Cyclodextrine were used as the water soluble carriers for increasing the solubility of Ziprasidone. All the inclusion complexes prepared by lyophilisation technique showed remarkable increase in the solubility compared to the pure Ziprasidone HCl. The saturation solubility analysis demonstrated highest increase in the solubility of drug after complexation with HP-β-CD by lyophilisation technique. The inclusion complexes were characterized using DSC and XRD technique. During in vitro study result obtained that the lyophilized complexes with HPβ-CD showed 100% drug release within 10 min were as the lyophilized complexes with β– CD showed 100% drug release in 25 min. Therefore the freeze dried complex with HP-β-CD was selected for Catalepsy study on Wistar rats. In the catalepsy study the selected inclusion complex showed increase in bioavailability compared to the drug and almost all the data obtained from study was found to be 99.99% significant with the control.

Keywords:

Bioavailability, Inclusion complex, Lyophilisation, Ziprasidone HCl

INTRODUCTION: ^1-7The way of treating psychosis was totally changed when atypical antipsychotics were introduced in the therapy of psychosis. Due to the economic and therapeutic efficacy of second generation antipsychotics these are preferred mostly for the treatment than first generation antipsychotics. Ziprasidone Hydrochloride (HCl) is one of the newly introduced atypical antipsychotic. It has its unique multi receptor binding affinity.

This makes it a unique special choice of antipsychotic agent. It mainly acts as antagonist of D2 dopamine and 5HT₂A (serotonin, 5HT, 5-hydroxytryptamine) receptors. It is a pinkish brown coloured powder having very low solubility in water (21.12 mg/L). The oral absorption of Ziprasidone is limited and it reaches maximum concentration within 6-7 hours. Therefore it shows poor oral bioavailability. The oral bioavailability is only 39-60% with a t_1/2of about 6 hours (Approximately). Complexing with cyclodextrin is one of the most promising techniques to enhance the solubility of poor water soluble moiety. They form a water soluble complex with the drug having very low solubility. The complexes were prepared using various techniques physical mixing, kneading, co-precipitation, solvent evaporation, spray drying and freeze drying. In present study β-Cyclodextrine and Hydroxy Propyl- β-Cyclodextrine were used as the water soluble carriers for increasing the solubility of Ziprasidone using lyophilisation technique. All inclusion complexes prepared by lyophilisation technique showed remarkable increase in the solubility compared to the pure Ziprasidone HCl. The saturation solubility analysis demonstrated highest increase in the solubility of drug after complexation with HP-β-CD by lyophilisation technique.

The inclusion complexes were characterized using DSC and XRD technique. The dissolution profiles were calculated and compared with different complexes. The influence of carriers and methods on complexation and physicochemical property of drug–CD complex was investigated to select the most efficient and effective system for improving solubility of Ziprasidone HCl.

MATERIALS AND METHODS: Ziprasidone HCl gift sample was provided by Micro labs Mumbai, India. Β-cyclodextrin (BCD) and HP β-CD was provided as gift sample by Gangwal Chemicals Mumbai, India. Other chemicals used were of analytical grade.

Phase Solubility Study: ⁸Solubility determinations were performed in triplicate according to the method of Higuchi and Connors. The effect of concentrations of the two Cyclodextrins on the equilibration solubility of Ziprasidone HCl in water at room temperature was carried out by adding an excess amount of drug (25 mg) in to a screw-capped glass vial containing 10 ml of water and various amounts of the carrier (2-10% w/v). The samples were placed on a magnetic stirrer and agitated at room temperature for 48 hrs. An aliquot of each solution was withdrawn and filtered through a Whatman filter paper (no. 41). The assay of Ziprasidone HCl was determined spectrophotometrically at 318 nm (Shimadzu U.V 1800). A plot of molar concentrations of each of β- CD and HPβ-CD vs. molar concentrations of drug was plotted. The stability constant was calculated according to equation:

K _(1:1)= Slope/ S_o (1-Slope)

Methods of preparation of Inclusion complexes: ^{9, 10, 11, 19, 21, 22, 23}

Physical Mixture:^{9, 10} The required molar (1:1) ratio quantities of drug and β-CD/Hp β-CD were weighed and mixed separately in mortar with vigorous trituration. The mixtures were then passed through sieve no. 40 and were stored in airtight container until further use.

Lyophilisation / Freeze drying:¹¹The earlier prepared 1:1 physical mixture of the drug was wetted with 1:1 water: methanol mixture and this was kneaded to form a homogeneous suspension. This was then frozen for 24 hrs at -21 ⁰C and subjected to lyophilisation. The final product was then pulverized and sieved between 50 μm and 200 μm sieves.

Characterization of Inclusion complexes:

Saturation Solubility: ^{12, 24}Solubility study was performed according to method reported by Higuchi and Connors. Excess quantities of inclusion complexes were added to 25 ml distilled water taken in stoppered conical flasks and mixtures were shaken for 24 hrs. After sufficient shaking to achieve equilibrium, 2 ml aliquots were withdrawn at 1 hr intervals and filtered through Whatman filter paper no. 41. The filtrate so obtained was analyzed spectrophotometrically at 318 nm. Shaking was continued until three consecutive readings were same.

Drug Content Determination: ¹³Drug content was determined by dissolving solid dispersion equivalent to 10 mg of the ZPR in small quantity of methanol and kept in ultrasonicator for 10 min. The volume was adjusted to 50ml with 1% SLS in phosphate buffer pH 7.4. The solution was filtered through Whatman filter paper no.41, suitably diluted and the absorbance was measured at 318 nm using double beam U.V. spectrophotometer (Shimadzu U.V 1800).

Infra-Red Analysis: ¹⁴IR absorption spectrum of Zip

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