Dissolution of ionizable water-insoluble drugs: The combined effect of pH and surfactant

Abstract

This study reports the results of the combined effect of pH and surfactant on the dissolution of piroxicam (PX), an ionizable water-insoluble drug in physiological pH. The intrinsic dissolution rate (J total ) of PX was measured in the pH range from 4.0 to 7.8 with 0%, 0.5%, and 2.0% sodium lauryl sulfate (SLS) using the rotating disk apparatus. Solubility (c total ) was also measured in the same pH and SLS concentration ranges. A simple additive model including an ionization (PX ↔ H + + PX − ) and two micellar solubilization equilibria (PX + micelle ↔ [PX] micelle , PX − + micelle ↔ [PX − ] micelle ) were considered in the convective diffusion reaction model. J total and c total of PX increased with increasing pH and SLS concentration in an approximately additive manner. Nonlinear regression analysis showed that observed experimental data were well described with the proposed model (r 2 ‫ס‬ 0.86, P < 0.001 for J total and r 2 ‫ס‬ 0.98, P < 0.001 for c total ). The pK a value of 5.63 ± 0.02 estimated from c total agreed well with the reported value. The micellar solubilization equilibrium coefficient for the unionized drug was estimated to be 348 ± 77 L/mol, while the value for the ionized drug was nearly equal to zero. The diffusion coefficients of the species PX, PX − , and [PX] micelle were estimated from the experimental results as (0.93 ± 0.35) × 10 −5 , (1.4 ± 0.30) × 10 −5 , and (0.59 ± 0.21) × 10 −5 cm 2 /s, respectively. The total flux enhancement is less than the total solubility enhancement due to the smaller diffusion coefficients of the micellar species. This model may be useful in predicting the dissolution of an ionizable water insoluble drug as a function of pH and surfactant and for establishing in vitro-in vivo correlations, IVIVC, for maintaining bioequivalence of drug products.

Build‐up of Polypeptide Multilayer Coatings with Anti‐Inflammatory Properties Based on the Embedding of Piroxicam–Cyclodextrin Complexes

“…The color of the crystals remaining on the bottom of the sample vials was white in presence of a cCD concentration above 4 10 ±4 M, whereas the color became yellow when the Px solubility was decreased in the presence of only small amounts of cCD (below 2 10 ±4 M). A color change from white to yellow during solubility determinations was already described by Jinno et al [20] and attributed to a crystal form conversion of Px from a neutral form (white) to a zwitterionic form (yellow).…”

“…Particles of 1.2 nm average diameter, which corresponds to the mean size of dimers or trimers, were apparently found at 1.654 10 ±3 M and relatively large aggregates (200 nm) were present at 8.27 10 ±3 M. Px solubility at pH 7.4 is about 10 ±5 M (3.5 lg mL ±1 ). [20] Despite its self-aggregation property, cCD can nevertheless solubilize significant amounts of Px (up to 6 10 ±4 M) when cCD concentration is less than about 1.6 10 ±3 M. The solubilization capacity of cCD is thus even more important than that of hydroxypropyl-b-cyclodextrin [18] or b-cyclodextrin, [17] commercial cyclodextrins, which increase the Px solubility level by a factor of 4 (about 4 10 ±5 M) and 5, respectively. However, when cCD starts to form aggregates, above 1.6 10 ±3 M, its guest-binding ability is hindered, as demonstrated on Figure 1.…”

The dissolution test in biorelevant media as a prognostic tool for modeling of drug behavior in vivo

“…в ряде исследований показали существенное влияние ПАВ на растворимость малорастворимых субстанций в условиях, моделирующих физиологические. На примере двух слабых кислот II класса БКС (кетопрофена и пироксикама) было установлено, что наибольший вклад в их растворимость ПАВ вносят при слабокислых и близких к нейтральным значениям рН: так, для кетопрофена прибавление к среде растворения 1,0% лаурилсульфата натрия повышало его растворимость в 17 раз при рН 4,0; в 3 раза при рН 6,0 и только в 1,25 раза при рН 6,8 [22,23].…”

Powder Dissolution Method for Estimating Rotating Disk Intrinsic Dissolution Rates of Low Solubility Drugs

“…During development, investigative IDR studies can be carried out with the traditional Wood's apparatus (4)(5)(6)(7)(8), consisting of rotating disks of compacted powder (~500 mg) of the active pharmaceutical ingredient (API) immersed in dissolution test media. Traditional six-vessel US Pharmacopeia (9) (USP) -specified dissolution baths are commonly used, accommodating thermostated (37°C) media (900 mL) in each vessel.…”