Excipient-Induced Lattice Disorder in Active Pharmaceutical Ingredient: Implications on Drug Product Continuous Manufacturing.

Our previous work (Mol Pharm, 20 (2023) 3427) showed that crystalline excipients, specifically anhydrous dibasic calcium phosphate (DCPA), facilitated the dehydration of carbamazepine dihydrate (CBZDH) and the formation of an amorphous product phase during the mixing stage of continuous tablet manufacturing. Understanding the mechanism of this excipient-induced effect was the object of this study. Blending with DCPA for 15 min caused pronounced lattice disorder in CBZDH.

Drug Phase Transformation and Water Redistribution during Continuous Tablet Manufacturing: A Case Study of Carbamazepine Dihydrate.

In recent years, continuous tablet manufacturing technology has been used to obtain regulatory approval of several new drug products. While a significant fraction of active pharmaceutical ingredients exists as hydrates (wherein water is incorporated stoichiometrically in the crystal lattice), the impact of processing conditions and formulation composition on the dehydration behavior of hydrates during continuous manufacturing has not been investigated. Using powder X-ray diffractometry, we monitored the dehydration kinetics of carbamazepine dihydrate in formulations containing dibasic calcium phosphate, anhydrous (DCPA), mannitol, or microcrystalline cellulose.

Understanding the role of magnesium stearate in lowering punch sticking propensity of drugs during compression.

The sticking of active pharmaceutical ingredient (API) to the surfaces of compaction tooling, frequently referred to as punch sticking, causes costly downtime or product failures in commercial tablet manufacturing. Magnesium stearate (MgSt) is a common tablet lubricant known to ameliorate the sticking problem, even though there exist exceptions. The mechanism by which MgSt lowers punch sticking propensity (PSP) by covering API surface is sensible but not yet experimentally proven.

Magnesium stearate surface coverage on tablets and drug crystals: Insights from SEM-EDS elemental mapping.

Scanning electron microscopy-based energy dispersive X-ray spectroscopy (SEM-EDS) is proposed as a versatile tool for quantifying surface area coverage (SAC) by magnesium stearate (MgSt) on pharmaceutical tablets and particles. Our approach involved fast elemental mapping and subsequent SAC quantitation by image analysis. The study was conducted using a multi-component system, but the particle-level mapping was limited to active pharmaceutical ingredient (API) crystals.

Toward a Molecular Understanding of the Impact of Crystal Size and Shape on Punch Sticking.

Punch sticking during tablet manufacturing is a common problem facing the pharmaceutical industry. Using several model compounds, effects of crystal size and shape of active pharmaceutical ingredients (API) on punch sticking propensity were systematically investigated in this work to provide molecular insights into the punch-sticking phenomenon. In contrast to the common belief that smaller API particles aggravate punch sticking, results show that particle size reduction can either reduce or enhance API punch sticking, depending on the complex interplay among the particle surface area, plasticity, cohesive strength, and specific surface functional groups.

Challenges in Transitioning Cocrystals from Bench to Bedside: Dissociation in Prototype Drug Product Environment.

Tablets containing a theophylline-glutaric acid (TG) cocrystal dissociated rapidly forming crystalline theophylline (20-30%), following storage at 40 °C/75% RH for 2 weeks. Control tablets of TG cocrystal containing no excipients were stable under the same conditions. The dissociation reaction was water-mediated, and the theophylline concentration (the dissociation product), monitored by synchrotron X-ray diffractometry, was strongly influenced by the formulation composition.

Effect of excipient properties, water activity, and water content on the disproportionation of a pharmaceutical salt.

Excipients are crucial components of most pharmaceutical formulations. In the case of a solid oral dosage formulation containing the salt form of a weakly ionizable drug, excipient selection is critical, as some excipients are known to cause salt disproportionation (conversion of salt to the free form). Therefore, robust formulation design necessitates an in-depth understanding of the factors impacting salt disproportionation during processing or storage as this can negatively impact product quality and performance.

Solid-State Characterization and Relative Formation Enthalpies To Evaluate Stability of Cocrystals of an Antidiabetic Drug.

The current study integrates formation enthalpy and traditional slurry experiments to quickly assess the physical stability of cocrystal drug substance candidates for their potential to support drug development. Cocrystals of an antidiabetic drug (GKA) with nicotinamide (NMA), vanillic acid (VLA), and ethyl vanillin (EVL) were prepared and characterized by powder X-ray diffractometry (PXRD), spectroscopic, and thermal techniques. The formation enthalpies of the cocrystals, and their physical mixtures (GKA + coformer) were measured by the differential scanning calorimetry (DSC) method reported by Zhang et al.

Impact of Solid-State Form on the Disproportionation of Miconazole Mesylate.

Approximately 50% of solid oral dosage forms utilize salt forms of the active pharmaceutical ingredient (API). A major challenge with the salt form is its tendency to disproportionate to produce the un-ionized API form, decreasing the solubility and negatively impacting product stability. However, many of the factors dictating the tendency of a given salt to undergo disproportionation remain to be elucidated.

Evaluation of the effect of new formulation, food, or a proton pump inhibitor on the relative bioavailability of the smoothened inhibitor glasdegib (PF-04449913) in healthy volunteers.

Purpose: This phase I open-label study investigated the oral bioavailability of two novel maleate salt-based glasdegib (PF-04449913) tablet formulations (small- and large-particle size) relative to the current clinical formulation (diHCl salt-based). In addition, the effect of a gastric pH-altering agent (rabeprazole) and food on the pharmacokinetics of the large-particle size formulation of glasdegib were evaluated. The pharmacokinetics of glasdegib oral solution was also assessed.

Mechanistic Insight into Caffeine-Oxalic Cocrystal Dissociation in Formulations: Role of Excipients.

Caffeine-oxalic acid cocrystal, widely reported to be stable under high humidity, dissociated in the presence of numerous pharmaceutical excipients. In cocrystal-excipient binary systems, the water mediated dissociation reaction occurred under pharmaceutically relevant storage conditions. Powder X-ray diffractometry was used to identify the dissociated products obtained as a consequence of coformer-excipient interaction.

Powder properties and compaction parameters that influence punch sticking propensity of pharmaceuticals.

Punch sticking is a frequently occurring problem that challenges successful tablet manufacturing. A mechanistic understanding of the punch sticking phenomenon facilitates the design of effective strategies to solve punch sticking problems of a drug. The first step in this effort is to identify process parameters and particle properties that can profoundly affect sticking performance.

Crystalline mesophases: Structure, mobility, and pharmaceutical properties.

Crystalline mesophases, which are commonly classified according to their translational, orientational, and conformational order as liquid crystals, plastic crystals, and conformationally disordered crystals, represent a common state of condensed matter. As an intermediate state between crystalline and amorphous materials, crystalline mesophases resemble amorphous materials in relation to their molecular mobility, with the glass transition being their common property, and at the same time possessing a certain degree of translational periodicity (with the exception of nematic phase), with corresponding narrow peaks in X-ray diffraction patterns. For example, plastic crystals, which can be formed both by near-spherical molecules and molecules of lower symmetry, such as planar or chain molecules, can have both extremely sharp X-ray diffraction lines and exhibit glass transition.

Use of in situ atomic force microscopy to follow phase changes at crystal surfaces in real time.

AFM of cocrystals: Atomic force microscopy can be used to observe phase changes at crystal surfaces where the transformation is accompanied by a change in the spacing between layers of molecules. The conversion of a metastable polymorph of the caffeine-glutaric acid cocrystal into the thermodynamically stable form was analyzed continuously in situ using intermittent-contact-mode atomic force microscopy.

Thermodynamic stability considerations for isostructural dehydrates.

Nonstoichiometric channel hydrates are a class of crystalline hydrates that can incorporate a range of water levels as a function of temperature and relative humidity (RH). When a nonstoichiometric channel hydrate can dehydrate to yield a physically stable isostructural crystalline lattice, it may become challenging to accurately evaluate the thermodynamic stability relationship associated with a polymorphic system using traditional methods. This work demonstrates application of a eutectic-melting method to determine the stability relationship between a nonstoichiometric channel dehydrate and an anhydrous form.

Crystalline, liquid crystalline, and isotropic phases of sodium deoxycholate in water.

Sodium deoxycholate (NaDC) is an important example of bile salts, representing systems with complex phase behavior involving both crystalline and mesophase structures. In this study, properties of NaDC-water mixtures were evaluated as a function of composition and temperature via X-ray diffraction with synchrotron (sXRD) and laboratory radiation sources, water sorption, polarized light, hot-stage microscopy, and freezing-point osmometry. Several phases were detected depending on the composition and temperature, including isotropic solution phase, liquid crystalline (LC) phase, crystalline hydrate, and ice.

Varenicline L-tartrate crystal forms: characterization through crystallography, spectroscopy, and thermodynamics.

This research utilized crystallographic, spectroscopic, and thermal analysis data to assess the thermodynamic stability relationship between the three known crystal forms of Varenicline L-tartrate. Of the two anhydrous forms (Forms A and B), Form B was determined to be the stable form at 0 K based on its calculated true density, hydrogen bonding in the crystal lattice, and application of the IR rule. Form A has a higher melting point and higher solubility at room temperature as compared to Form B, indicating that these forms are enantiotropically related.

Identification of phase boundaries in anhydrate/hydrate systems.

Near-infrared spectroscopy was used to monitor the phase conversion for two solvatomorphs of caffeine, an anhydrous form and a nonstoichiometric hydrate, as a function of time, temperature, and relative humidity. The transformation kinetics between these caffeine forms was determined to increase with temperature. The rate of conversion was also determined to be dependent on the difference between the observed relative humidity and the equilibrium water activity of the anhydrate/hydrate system, that is, phase boundary.