Search

Mesoporous silica particles are attractive carriers for poorly soluble drugs whereby confinement of drugs in the mesopores leads to amorphization, which makes them potential carriers for enhanced oral delivery. However, interactions between the drug molecules and the silica surface can lead to incomplete drug release. The strength of the interaction depends on the silica surface chemistry, which varies as a function of pH, as well as on drug chemistry and ionization states. Herein, the adsorption and dissolution behavior of weakly basic drugs were evaluated as a function of pH to understand the impact of electrostatic interactions on the performance of mesoporous silica-based formulations. A higher adsorption was noted when the drug interacted with the silica surface via electrostatic interactions compared to hydrogen bonding. Higher adsorption, in turn, led to a lower extent of drug release. In two-stage release studies of drugs with p K a values close to the intestinal pH, a shift from low to higher pH solutions resulted in a decrease in the solution concentration. Further investigations demonstrated that this was due to readsorption of the drug, initially released in the acidic medium when the pH was increased. Two-stage release studies were also coupled with mass transport measurements. Only a slight improvement in drug release due to simultaneous absorption across a membrane was observed, suggesting strong drug adsorption to the silica surface arising from favorable electrostatic interactions, which diminishes the effect of sink conditions provided by the absorptive environment. This study highlights that physiological parameters, such as solution pH, are important considerations when designing mesoporous silica-based formulations for poorly soluble drugs. It also underscores the importance of incorporating in vivo-relevant conditions in in vitro testing to better evaluate these complex formulations due to the notable effect of dissolution media on the release behavior.

In the recent years, coamorphous systems, containing an active pharmaceutical ingredient (API) and a small molecule coformer have appeared as alternatives to the use of either amorphous solid dispersions containing polymer or cocrystals of API and small molecule coformers, to improve the dissolution and oral bioavailability of poorly soluble crystalline API. This Commentary article considers the relative properties of amorphous solid dispersions and coamorphous systems in terms of methods of preparation; miscibility; glass transition temperature; physical stability; hygroscopicity; and aqueous dissolution. It also considers important questions concerning the fundamental criteria to be used for the proper selection of a small molecule coformer regarding its ability to form either coamorphous or cocrystal systems. Finally, we consider various aspects of product development that are specifically associated with the formulation of commercial coamorphous systems as solid oral dosage forms. These include coformer selection; screening; methods of preparation; preformulation; physical stability; bioavailability; and final formulation. Through such an analysis of coamorphous API-small molecule coformer systems, against the more widely studied API-polymer dispersions and cocrystals, it is believed that the strengths and weaknesses of coamorphous systems can be better understood, leading to more efficient formulation and manufacture of such systems for enhancing oral bioavailability., (Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Computational crystal structure prediction (CSP) methods can now be applied to the smaller pharmaceutical molecules currently in drug development. We review the recent uses of computed crystal energy landscapes for pharmaceuticals, concentrating on examples where they have been used in collaboration with industrial-style experimental solid form screening. There is a strong complementarity in aiding experiment to find and characterise practically important solid forms and understanding the nature of the solid form landscape.

Solid-form screening to identify all solid forms of an active pharmaceutical ingredient (API) has become increasingly important in ensuring the quality by design of pharmaceutical products and their manufacturing processes. However, despite considerable enlargement of the range of techniques that have been shown capable of producing novel solid forms, it is possible that practically important forms might not be found in the short timescales currently allowed for solid-form screening. Here, we report on the state-of-the-art use of computed crystal energy landscapes to complement pharmaceutical solid-form screening. We illustrate how crystal energy landscapes can help establish molecular-level understanding of the crystallization behavior of APIs and enhance the ability of solid-form screening to facilitate pharmaceutical development., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Elucidating the crystal structures, transformations, and thermodynamics of the two zwitterionic hydrates (Hy2 and HyA) of 3-(4-dibenzo[b,f][1,4]oxepin-11-yl-piperazin-1-yl)-2,2-dimethylpropanoic acid (DB7) rationalizes the complex interplay of temperature, water activity, and pH on the solid form stability and transformation pathways to three neutral anhydrate polymorphs (Forms I, II°, and III). HyA contains 1.29 to 1.95 molecules of water per DB7 zwitterion (DB7z). Removal of the essential water stabilizing HyA causes it to collapse to an amorphous phase, frequently concomitantly nucleating the stable anhydrate Forms I and II°. Hy2 is a stoichiometric dihydrate and the only known precursor to Form III, a high energy disordered anhydrate, with the level of disorder depending on the drying conditions. X-ray crystallography, solid state NMR, and H/D exchange experiments on highly crystalline phase pure samples obtained by exquisite control over crystallization, filtration, and drying conditions, along with computational modeling, provided a molecular level understanding of this system. The slow rates of many transformations and sensitivity of equilibria to exact conditions, arising from its varying static and dynamic disorder and water mobility in different phases, meant that characterizing DB7 hydration in terms of simplified hydrate classifications was inappropriate for developing this pharmaceutical.

The amount of water vapor taken up by an active pharmaceutical ingredient (API) as a function of relative humidity is routinely evaluated to characterize and monitor its "hygroscopicity" throughout the drug development process. In this minireview we address the necessity of going beyond the measurement of water vapor sorption isotherms to establish the various mechanisms by which solids interact with water and the important role played by the crystalline or amorphous form of the solid. Practical approaches for choosing experimental conditions under which water vapor sorption should be measured, including the pre-treatment of samples and the time allowed to reach an equilibrium state are presented. With the assistance of a flowchart, we provide a basis for the systematic examination of samples to establish the likely mechanisms of sorption and the indicators pointing toward future problems with physical and chemical instabilities. Finally, we present strategies for managing materials that might be susceptible to the detrimental effects of water vapor sorption., ((Copyright) 2008 Wiley-Liss, Inc.)

Controlling the appearance of crystal polymorphs of pharmaceuticals is essential in developing robust large-scale crystallization processes in the pharmaceutical industry. This review describes many of the thermodynamic and kinetic factors that are important for controlling crystal polymorphism and discusses recent advances in the understanding of the molecular mechanisms of polymorph appearance. Case studies in the development of crystallization processes of pharmaceutical solids, where process analytical technology was applied to resolve the complexities introduced by crystal polymorphism, are discussed.

Quantitative analysis of solid state composition is often used to ensure the safety and efficacy of drug substances or to establish and validate the control of the pharmaceutical production process. There are a number of common techniques that can be applied to quantify the phase composition and numerous different methods for each technique. Each quantitative option presents its own issues in ensuring accuracy and precision of the solid state method. The following article describes many of the common techniques that are used for quantitative phase analysis and many of the considerations that are necessary for the development of such methods.