Comparison of Biorelevant and Compendial Dissolution Media and Prediction of In-vivo Plasma Profile of BCS Class II Drug.

Manju Nagpal^1*, Pankaj Rakha^1, Surinder Goyal¹, Gitika Dhingra²and Sunil Gupta³

¹Rajendra Institute of Tech. and Sciences, Sirsa, Haryana, India

²NCRD’s Sterling Institute of Pharmacy, Navi Mumbai, India

³Glaxosmithcline Pvt. Ltd. Mumbai, India

ABSTRACT

The performance of biorelevant and compendial media was compared to test dissolution of drugs belonging to class II according to Biopharmaceutic Classification Scheme (BCS) and their potential was determined in predicting in-vivo profile. The solubility of Carbamazepine was determined in various media having different pH (water, SGF_SP, SIF_SP, SGF_SPSLS, FaSSIF and FeSSIF), to calculate D/S values in different media. Dissolution of Carbamazepine, a neutral drug was studied using USP apparatus II in water, SGF_SP, SIF_SP, SGF_SPSLS, FaSSIF and FeSSIF. Hixson- Crowell model was applied to determine drug release kinetics. The invivo profile was predicted from invitro dissolution data using modified form of model proposed by Nicolaides in 2001. Dissolution of Carbamazepine from tablet formulation was found to be dependent upon concentration of solubilizing agents. The similarity factor indicated pH independent dissolution of carbamazepine in different dissolution media. The invivo profiles predicted using invitro dissolution of carbamazepine in biorelevant media supported better absorption in the presence of food which matches the literature facts. The Biorelevant Media therefore are better at discriminating invitro release characteristics for forecasting invivo performance of poorly soluble drugs.

KEYWORDS: Biorelevant media, FaSSIF, FeSSIF, BCS.

INTRODUCTION

The in-vitro dissolution testing of solid oral dosage forms is used to assess release of drug and facilitates appropriate selection of excipients during formulation development. The use of dissolution testing of solid oral dosage forms to establish correlation between release of drug invitro and absorption of drug in-vivo from GIT avoids need for costly bioavailability studies. Satisfactory in-vitro in-vivo correlation can be established for BCS¹ class II drugs because dissolution rate is limiting aspect to absorption. A dissolution test with multiple time points is required to simulate bioavailability². Food exerts a complex influence on the bioavailability of drug from GIT. The presence of food may alter drug absorption due to interaction with specific food components or due to change in GI physiological parameters during fasted and fed states. The solubility and absorption of poorly water-soluble drugs is influenced by physiological variation of bile salt concentration and pH during fed and fasted states³. The mean value of conjugated bile acids during fasting, 30 min. postprandial and 60 min. postprandial are 5mM, 15mM and 8mM respectively⁴. During fasted state, pH of duodenum is 6.1±0.4 and during fed state duodenum pH fluctuates around 5.3±0.4⁵. The composition of dissolution media, volume and hydrodynamics of contents in the lumen following administration of the dosage form are the main factors that affect dissolution of drug in GIT. The dissolution rate limited absorption can be accurately predicted only when these factors are adequately controlled and reproduced invitro.

Fig 1:Scheme of the model used to obtain simulation profiles⁸.

RESULTS:

Table 1: D/S Values of Carbamazepine in various dissolution media.

Dissolution Media (pH)	D/S
Distilled Water	2.0
SGF_SP (1.2)	2.0
SIF_SP (7.5)	2.5
SGF_SPSLS (1.48)	2.0
FaSSIF(6.5)	1.0
FeSSIF(5.0)	0.6

Fig 2: Dissolution profiles of carbamazepine in various dissolution media.

The objective of present study was to compare biorelevant and compendial media on the basis of D/S values and dissolution of carbamazepine (neutral pK_a and log P =2.45) and to predict invivo plasma profiles of carbamazepine from invitro dissolution.

MATERIALS AND METHODS:

Carbamazepine (Mazetol Tablets – Sarabhai Piramal Pharmaceuticals Limited), Lecithin (Kaushambi Enterprises, Varanasi), Sodium Taurocholate (CDH, New Delhi), Potassium Dihydrogen Phosphate, Sodium Lauryl Sulfate.

Determination of D/S value:

The solubility was determined in compendial and biorelevant media by adding known amount of drug (10, 20, 30, 40 and 50 mg) in different volumes (100,500 and 1000ml) of dissolution media and incubated in shaker incubator at 37±0.5 °C. The ionic strength of all media was adjusted to 0.15 N using sodium chloride⁹. The D/S values for each media were obtained from solubility corresponding to second highest absorbance in the range of 0.2-0.8. These solutions also served as stock for the preparation of calibration curve. The weighted regression was used to derive coefficients (slope and intercept) of calibration curve¹⁰.

b = {SWXY-(SWX*SWY/SW)}/{SWX²-(SWX*SWY/SW)}

a = Y_W-b*X_W

Where, Y_W= SWY/SW, X_W = SWX/SW and Weight (W) = 1/ (concentration)²

The composition of compendial dissolution media does not discriminate between fasted and fed state. Therefore, compendial dissolution media (SGF_SPand SIF_SP) are best suited for quality control purpose but can not be used for IVIVC in all cases². Biorelevant dissolution media⁶ not only distinguish between formulations with different bioavailability but also predict food effects on drug absorption⁷. The invitro dissolution testing of BCS class II drugs in biorelevant dissolution media determine qualitative aspects of formulation and food effects on absorption of these drugs. The invivo profile from invitro data can be predicted if drug exhibits dissolution rate limited absorption and absolute bioavailability of drug is known⁸.

Dissolution test:

The USP apparatus II (paddle method) containing 500 ml of dissolution media (both compendial and biorelevant), maintained at 37±0.5°C and stirred at 100 rpm, was used to analyze 12 units per test. The aliquots (2ml) were withdrawn at different intervals up to 2 hrs and filtered through 0.45 m filter. The drug content was measured spectrophotometrically (Beckman, D4 640B, USA) at 284 nm in all dissolution media except SGF_SPSLS where l_max was 287 nm. The invitro dissolution profile was explained by Hixson-Crowell model which is given by following expression:

M_o^1/3- M^1/3 = Kt

Where, M_o= original mass of drug particle, M = amount of drug release, t = time and K = dissolution rate constant¹¹. Dissolution test was used to compare the discriminating ability of biorelevant and compendial media. The f₂ factor was calculated from the following equation¹²:

f₂ = 50 log [{1 + 1/n S(T₁- T₂)²}^0.5 *100]

Where, T₁ and T₂= percent drug dissolved at each time point in two different dissolution media and n = number of observations. An f₂value less than 50 indicate different dissolution profiles.

Table 2: Similarity factor values of carbamazepine amongst different media.

	SGF_SP	SIF_SP	D.WATER	SGF_SPSLS	FaSSIF	FeSSIF
SGF_SP
SIF_SP	58
D.WATER	76	65
SGF_SPSLS	31	26	29
FaSSIF	24	20	22	51
FeSSIF	17	14	16	32	47

SGF_SP + SIF_SP

SGF_SPSLS + FeSSIF

Fig 3: Predicted Plasma profiles of carbamazepine in (a) SGF_SP+ SIF_SP(b) SGF_SPSLS +FaSSIF (c) SGF_SPSLS +FeSSIF

Prediction of in-vivo plasma profile:

The plasma profiles were predicted from invitro dissolution data using the model which is based upon different assumptions like negligible gastric uptake, simultaneous liquid and gastric emptying from the stomach and no intestinal permeability restrictions. The initial volume of the fluid in the stomach was assumed to be 250 ml in fasted state and 500 ml in fed state. The average population values for gastric emptying rate were used i.e. first order gastric emptying rate in fasted state (2.8hr^-1)_. The amount of drug entering the plasma was estimated from the product of drug in intestine and bioavailability. The sink conditions were assumed for dissolution in intestine⁸.

DISCUSSION:

The lowest D/S value in Biorelevant media, FeSSIF and highest D/S value in compendial media,¹³ SIF_SPreflect maximum and minimum solubility of carbamazepine respectively (Table1). The solubility of carbamazepine being higher in FeSSIF than in FaSSIF is attributed to higher concentration of bile salts and lecithin in FeSSIF, which lead to greater solubilization via reduction in surface tension¹⁴. However, the pH of dissolution medium did not play any role.

The dissolution of carbamazepine was maximum in FeSSIF followed by FaSSIF, SGF_SPSLS, SGF_SP¹³, water and SIF_SP(Fig 3). The extent of carbamazepine release is maximum in biorelevant media (SGF_SPSLS, FaSSIF and FeSSIF)^6,15,16 as compared to compendial dissolution media (SGF_SP, SIF_SP and water)¹³ which is attributed to surfactant effect of SLS/bile salts and is strengthened by higher extent of carbamazepine release in (a) FeSSIF than in FaSSIF, (b) SGF_SPSLS than in SGF_SP. The higher rate of carbamazepine release in biorelevant media than in compendial dissolution media is attributed to increased wetting of tablets due to lowering of surface tension by the surfactants¹⁴. This is further supported by higher rate of carbamazepine release in FeSSIF than in FaSSIF.

The dissolution of carbamazepine exhibited similarity value of more than 50 in all compendial media indicates that pH of compendial media did not discriminate dissolution profile of carbamazepine in water, SGF_SP and SIF_SP. And in case of biorelevant media it exhibited similarity factor value less than 50 except in case of FaSSIF and SGF_SPSLS (Table 2). The less value of similarity factor was due to significantly higher dissolution (due to higher surfactant concentration) of carbamazepine in FeSSIF than in SGF_SPSLS and FaSSIF. The different pH of SGF_SPSLS and FaSSIF did not discriminate between dissolution of carbamazepine which leads to similarity factor of more than 50. The dissolution of carbamazepine in biorelevant media was significantly different from dissolution in compendial media due to the absence of physiologically relevant substances in compendial media (similarity factor values of less than 50)¹⁷.

The invivo plasma profiles of carbamazepine predicted using invitro dissolution profiles in FeSSIF, FaSSIF and SIF_SP approached plateau level with in 4hrs, 8hrs and >15hrs respectively. Though the predicted C_max was similar in all media, the time to achieve plateau levels coincided with literature value in case of biorelevant media. The predicted plasma profile also support that absorption of carbamazepine is better when administered in the presence of food¹⁸ (Melander, 1978).

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Received on 06.06.2009

Accepted on 11.08.2009

Research Journal of Pharmaceutical Dosage Forms and Technology. 2(1): Jan. –Feb. 2010, 37-40