Shoufeng Li

Investigation of solubility and dissolution of a free base and two different salt forms as a function of pH

No HeadingPurpose.To evaluate the effect of pH on solubility and dissolution rates of a model weak base, haloperidol, and two different salt forms, hydrochloride and mesylate.Methods.pH-solubility profiles were determined by using haloperidol base, haloperidol hydrochloride, and haloperidol mesylate as starting materials; concentrated or diluted HCl or NaOH solutions were added to aqueous suspensions of solids to adjust pH to desired values. Intrinsic dissolution rates were determined using intrinsic dissolution apparatus under various pH-stat conditions. Further, approximation of diffusion layer pH was estimated from that of 10% w/w slurries of drug substances in dissolution media, which were used to correlate with intrinsic dissolution rates of haloperidol and its salt forms under different pHs.Results.pH-solubility profiles of haloperidol base and its HCl salt were similar, while when the mesylate salt was used as starting material, it exhibited a higher solubility between pH 2 and 5. The higher solubility of the mesylate salt at pH 2–5 is attributed to its higher solubility product (Ksp) than that of the hydrochloride salt. The pH-solubility profiles indicated a pHmax (pH of maximum solubility) of ∼5, indicating that the free base would exist as the solid phase above this pH and a salt would be formed below this pH. Below pH 1.5, all solubilities were comparable due to a conversion of haloperidol base or the mesylate salt to the HCl salt form when HCl was used as the acidifying agent. These were confirmed by monitoring the solid phase by differential scanning calorimeter. When their dissolution rates are tested, dissolution rates of the mesylate salt were much higher than those of the free base or the HCl salt, except at very low pH (<2). Dissolution rates of free base and HCl salt also differed from each other, where that of HCl salt exhibits higher dissolution rates at higher pHs. A direct correlation of dissolution rate with solubility at diffusion layer pH at the surface of dissolving solid was established for haloperidol, its hydrochloride, and mesylate salts.Conclusions.Using pH-solubility and pH-dissolution rate interrelationships, it has been established that diffusion layer pH could be used to explain the observed rank order in dissolution rates for different salt forms. A non-hydrochloride salt, such as a mesylate salt, may provide advantages over a hydrochloride salt due to its high solubility and lack of common ion effect unless at very low pH.

Correlation and Prediction of Moisture-Mediated Dissolution Stability for Benazepril Hydrochloride Tablets

AbstractPurpose. This report investigated dissolution stability of benazepril hydrochloride tablets. Methods. Reduction in dissolution rate was observed for benazepril hydrochloride tablets when they were subjected to stressed storage condition (40°C/75% RH) for prolonged periods of time (1-3 months). Moisture contents of initial and stressed tablets were measured by Karl Fischer method. Comparative thermal and physical characterizations of initial and stressed tablets were also performed. A mathematical model that was used to predict possible reduction in dissolution rate was proposed and validated using experimental data. Results. It was found that there was a direct correlation between moisture content of benazepril hydrochloride tablets and their percentage of dissolution at 10 min. At moisture content below 3.5%, there were no significant changes in dissolution values. Beyond that point, however, a close to linear decrease in dissolution was observed as a function of increase in moisture content. Results from thermal and X-ray analysis have ruled out possible changes in drug substance. Other physical characterization, such as scanning electron microscope and mercury porosimetry measurements, revealed changes in core structure of stressed tablets vs. initial tablets. Based on results from these measurements, “preactivation” of disintegrant was identified as the mechanism for reduction in dissolution rate above critical moisture content. A simple physical model for moisture uptake of benazepril hydrochloride tablets was also proposed for predicting when, based on water vapor transmission and critical moisture content, dissolution rate will decline. Conclusions. Physical changes of tablets mediated by moisture were the main cause for reduction in dissolution. Inclusion of desiccant, although beneficial, cannot prevent reduction in dissolution completely. The simple physical model proposed in this report was found to be useful in predicting the dissolution stability of the dosage form.

In Vitro–In Vivo Correlation in Dosage Form Development: Case Studies

In vitro and in vivo correlation (IVIVC) refers to a predictive relationship of the in vitro properties of drug substances or dosage forms with their in vivo performance. For orally administered drug products, it is usually a correlation between the extent or rate of dissolution of a dosage form and its pharmacokinetic parameters, such as rate, duration, and extent of drug absorption. The physicochemical properties of dosage forms influence their in vivo performance in many different ways (Li et al., 2005). Through the establishment of a definitive relationship between certain physicochemical properties of a dosage form with the in vivo appearance of its active component, one can establish in vitro testing criteria which will predict, its in vivo performance. Although IVIVC may be applied to many different types of dosage forms, including topical patches, various injectable forms like microparticulates and depot systems, and different inhalation formulations, the primary purpose of this chapter is to illustrate how the IVIVC concept can be applied to the development of oral dosage forms. IVIVC of oral dosage forms can also help in setting dissolution specifications and in applying in vitro data as surrogates for bioequivalence testing in case of certain preand postapproval changes (Center for Drug Evaluation and Research, US FDA, 1997). However, the drug product development is a continuous process with increasing physicochemical and pharmacokinetic data being available as it progresses from the early-stage to the late-stage development including life cycle management (LCM). For this reason, the IVIVC should also be a continuous process with more predictability built into it as the product development progresses. IVIVC has normally been studied for prototype formulations or finished dosage forms, where it involves at least two different formulations and a reference treatment, such as a solution or immediate-release formulation. The formulation properties used must have significantly different in vitro or in vivo profiles (>10%). The correlation established based on such studies may be categorized into Levels A, B, and C (United States Pharmacopeial Convention, Inc., 1988),