Development and validation of an in vitro–in vivo correlation for extended

buspirone HCl release tabletsSevgi Takka, Adel Sakr and Arthur Goldberg

Journal of Controlled Release

Volume 88, Issue 1, 14 February 2003, Pages 147-157

Objective

• According to the Biopharmaceutics classification system, buspirone hydrochloride can be classified as a “Class 1” drug, i.e., high solubility and permeability.

• In addition, it is a highly variable drug, exhibiting a very high first pass metabolism and only about 4% of an orally administered dose will reach the systemic circulation unchanged after oral administration.

• Therefore, the purpose of this study was to develop an IVIVC for a novel hydrophilic matrix extended release buspirone hydrochloride tablets.

Formulation

• Extended release formulations of buspirone hydrochloride were developed using hydroxypropyl methylcellulose (HPMC) as one of the release rate controlling excipients, and Eudragit L100-55 as the other controlled release polymer, and included silicified microcrystalline cellulose as filler, and magnesium stearate as lubricant.

• The formulations were designed to release buspirone hydrochloride at two different rates referred to as “Slow” and “Fast”. The high-viscosity HPMC (Methocel K100M) and the low-viscosity HPMC (Methocel K100LV) are used for slow and fast release, respectively

Dissolution Testing

• The release characteristics of the formulations were determined using USP Apparatus II, at 50 and 100 rpm, in 0.1 M HCl or pH 6.8 phosphate buffer maintained at 37 °C.

• Dissolution tests were performed on six tablets and the amount of drug released was analyzed spectrophotometrically at a wavelength of 238 nm.

• Dissolution samples were collected at the following times: 0, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10, 12 and 24 h.

Dissolution Testing

• Cumulative buspirone hydrochloride release versus time profile for “Slow” and “Fast” extended release tablets using (a) pH 6.8, 50 rpm, (b) 0.1 M HCl, 50 rpm, (c) pH 6.8, 100 rpm, (d) 0.1 M HCl, 100 rpm.

Dissolution Testing

• Cumulative buspirone hydrochloride release versus square root of time profile for “Slow” and “Fast” extended release tablets using (a) pH 6.8, 50 rpm, (b) 0.1 M HCl, 50 rpm, (c) pH 6.8, 100 rpm, (d) 0.1 M HCl, 100 rpm.

Dissolution Testing• It is observed that the high-molecular-weight (high

viscosity) polymer has a slower dissolution rate than the dosage form with the lower-molecular-weight (lower viscosity) polymer in both pH media.

• The release of buspirone hydrochloride from the slow and fast formulations were expected to be almost indistinguishable from each other when the dissolution is measured in 0.1 M HCl based on high solubility of drug in acidic media, but f2 values were 42.2 and 47.7 at 50 and 100 rpm, respectively.

• However, at pH 6.8, the differences between the formulations were more evident. Weakly basic buspirone hydrochloride has a lower solubility in pH 6.8 phosphate buffer than in 0.1 M HCl. The calculated similarity factors (f2) confirmed the conclusion

Dissolution Testing

Dissolution Testing• pH 6.8 phosphate buffer at both 50 and 100 rpm were

found to be the more discriminating dissolution media in our study and 50 rpm in phosphate buffer was then used in the IVIVC model development.

• Release profiles were compared using the similarity factor f2.

• f2 is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent of dissolution between the two curves.

• The similarity factor is 100 when the test and reference profiles are identical and approaches zero as the dissimilarity increases.

100

11log50

5.0

1

22

n

ttt TR

nf

Dissolution Testing• DTZ release from different formulations was also fitted to

the Higuchi:

• Where Mt/M∞ is the fraction of drug released at time t and k is the apparent release rate constant.

5.0ktM

M t

Bioavailability study

• An open-label, fasting, single dose, three-treatment crossover study using normal healthy volunteers.

• Eighteen male, non-smoking volunteers were enrolled in the study and received two extended release, once-per-day, formulations (slow and fast) of buspirone hydrochloride (30 mg) in a randomized fashion.

• In addition to the extended release formulations, an immediate release (2×15 mg) of buspirone hydrochloride (BUSPAR®) was also administered.

Bioavailability study

• The order of treatment administration was randomized in three sequences (ABC, BCA, CAB) in blocks of three.

• Blood samples were obtained at 22 time points from pre-dose (0 h) until 36 h post-dose. A washout period of 1 week was allowed between dose administrations.

• Subjects fasted for 12 h prior to the morning drug administration when the extended and immediate release products were administered, and for 4 h prior to the evening drug administration of the immediate release product.

Bioavailability study

Bioavailability study

• There are discernible differences in the plasma level concentrations between the three dosage forms (“Slow”, “Fast” and IR tablets).

• It was also found that the rank order of release observed in the dissolution testing was also apparent in the plasma buspirone hydrochloride concentration profiles with a mean Cmax of 1.37 and 1.76 ng/l for the slow and fast releasing formulations.

• However, the same rank order was not observed in the

AUC∞

Bioavailability study

Bioavailability study

• There is no significant or noticeable difference in the AUC from the slowest releasing dosage form compared to the fast releasing dosage form, showing that the extent of absorption of buspirone was the same despite the differences in release rates between the two dosage forms.

• The AUC of buspirone was much higher from the extended release forms than from the IR tablets.

In vivo data analysis • The measured plasma concentrations were used to

calculate the area under the plasma concentration–time profile from time zero to the last concentration time point (AUC(0–t)).

• The AUC(0–t) was determined by the trapezoidal method. AUC(0–∞) was determined by the following equation:

• ke was estimated by fitting the logarithm of the concentrations versus time to a straight line over the

observed exponential decline.

In vivo data analysis • The Wagner–Nelson method was used to calculate the

percentage of the buspirone hydrochloride dose absorbed:

• where F(t) is the amount absorbed. The percent absorbed is determined by dividing the amount absorbed at any time by the plateau value, keAUC(0–∞) and multiplying this ratio by 100:

In-vitro–in-vivo correlation • The data generated in the bioavailability study were used

to develop the IVIVC.

• The percent of drug dissolved was determined using the aforementioned dissolution testing method and the fraction of drug absorbed was determined using the method of Wagner–Nelson.

In-vitro–in-vivo correlation • The dissolution rate constants were determined from %

released vs. the square root of time.

• Linear regression analysis was applied to the in-vitro–in-vivo correlation plots and coefficient of determination (r2), slope and intercept values were calculated.

In-vitro–in-vivo correlation • Level A in-vitro–in-vivo correlation was investigated

using the percent dissolved vs. the percent absorbed data for both the slow and fast formulations, using both 0.1 M HCl and pH 6.8 phosphate buffer dissolution media at both 50 and 100 rpm.

• A good linear regression relationship was observed between the dissolution testing using pH 6.8 phosphate buffer at 50 rpm and the percents absorbed for the combined data of the two dosage forms

• Another good linear regression relationship was observed between the dissolution testing using 0.1 M HCl as the dissolution media at 50 rpm, and the percents absorbed for the combined data of the two dosage forms

In-vitro–in-vivo correlation

In-vitro–in-vivo correlation • It is also observed that the in-vivo absorption rate

constant (ka) correlates well with the pH 6.8 phosphate buffer in-vitro dissolution rate constant (kdiss), exhibiting a correlation coefficient of 0.9353.

• This was a better correlation than was obtained using the dissolution rates in 0.1 M HCl, and therefore, pH 6.8 phosphate buffer was selected as the dissolution media of choice.

In-vitro–in-vivo correlation

Plot of in vitro dissolution rate (kdiss) versus in vivo absorption rate (ka) constants

(The zero–zero point is theoretical).

Internal validation of the IVIVC • The internal predictability of the IVIVC was examined by

using the mean in-vitro dissolution data and mean in-vivo pharmacokinetics of the extended matrix tablets.

Internal validation of the IVIVC • The prediction of the plasma buspirone hydrochloride

concentration was accomplished using the following curve fitting equation:

• where, y=predicted plasma concentration (ng/ml); Const.=the constant representing F/Vd, where F is the fraction absorbed, and Vd is the volume of distribution; ka: absorption rate constant; ke: overall elimination rate constant.

• The de-convolution was accomplished on a spread-sheet in Excel®.

Internal validation of the IVIVC • To further assess the predictability and the validity of the

correlations, we determined the observed and IVIVC model-predicted Cmax and AUC values for each formulation. The percent prediction errors for Cmax and AUC were calculated as follows:

• where Cmax(obs) and Cmax(pred) are the observed and IVIVC model-predicted maximum plasma concentrations, respectively; and AUC(obs) and AUC(pred) are the observed and IVIVC model-predicted AUC for the plasma concentration profiles, respectively.

Internal validation of the IVIVC

• Observed and predicted buspirone hydrochloride plasma concentration for the (A) “Fast” and (B) “Slow” releasing formulation using the IVIVC model.

Internal validation of the IVIVC

External validation of the IVIVC • The external validation was accomplished by re-

formulating the extended release dosage form to a release rate between the “Fast” and the “Slow” rates, selected to provide a Cmax of the re-formulated product equivalent to the Cmax obtained from the IR tablets, and to re-test the re-formulated product against the IR tablets in another bioequivalence test in human subjects.