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. This was evident from the 190% increase in the apparent lattice strain determined by the Williamson-Hall plot. The rapid dehydration was attributed to the increased reactivity of CBZDH caused by this lattice disorder. Lattice disorder in CBZDH was induced by a second method, cryomilling it with DCPA. The dehydration was accelerated in the milled sample. Annealing the cryomilled sample reversed the effect, thus confirming the effect of lattice disorder on the dehydration kinetics. The hardness of DCPA appeared to be responsible for the disordering effect. DCPA exhibited a similar effect in other hydrates, thereby revealing that the effect was not unique to CBZDH. However, its magnitude varied on a case-by-case basis. The high shear powder mixing was necessary for rapid and efficient powder mixing during continuous drug product manufacturing. The mechanical stress imposed on the CBZDH, and exacerbated by DCPA, caused this unexpected destabilization.

Tale of Two Polymorphs: Investigating the Structural Differences and Dynamic Relationship between Nirmatrelvir Solid Forms (Paxlovid).

Two anhydrous polymorphs of the novel antiviral medicine nirmatrelvir were discovered during the development of Paxlovid, Pfizer's oral Covid-19 treatment. A comprehensive experimental and computational approach was necessary to distinguish the two closely related polymorphs, herein identified as Forms 1 and 4. This approach paired experimental methods, including powder X-ray diffraction and single-crystal X-ray diffraction, solid-state experimental methods, thermal analysis, solid-state nuclear magnetic resonance and Raman spectroscopy with computational investigations comprising crystal structure prediction, Gibbs free energy calculations, and molecular dynamics simulations of the polymorphic transition. Forms 1 and 4 were ultimately determined to be enantiotropically related polymorphs with Form 1 being the stable form above the transition temperature of ∼17 °C and designated as the nominated form for drug development. The work described in this paper shows the importance of using highly specialized orthogonal approaches to elucidate the subtle differences in structure and properties of similar solid-state forms. This synergistic approach allowed for unprecedented speed in bringing Paxlovid to patients in record time amidst the pandemic.

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. The combined effect of nitrogen flow and vigorous mixing during the continuous mixing stage of tablet manufacture facilitated API dehydration. Dehydration was rapid and most pronounced in the presence of DCPA. The dehydration product, amorphous anhydrous carbamazepine, sorbed a significant fraction of the water released by dehydration. Thus, the dehydration process resulted in a redistribution of water in the powder blend. The unintended formation of an amorphous dehydrated phase, which tends to be much more reactive than its crystalline counterparts, is of concern and warrants further investigation.

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. Therefore, other factors, such as crystal mechanical properties, surface chemistry of crystal facets exposed to the punch face, and choice of excipients in a formulation, should be considered for a more reliable prediction of the initiation and progression of punch sticking. The exposure of strong electronegative groups to the punch face facilitates the onset of sticking, while higher plasticity and cohesive strength aggravate sticking.

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. Investigation of the binary compacts of the TG cocrystal with each excipient revealed the influence of excipient properties (hydrophilicity, ionizability) on cocrystal stability, providing mechanistic insights into a dissociation reaction. Ionizable excipients with a strong tendency to sorb water, for example, sodium starch glycolate and croscarmellose sodium, caused pronounced dissociation. Microcrystalline cellulose (MCC), while a neutral but hydrophilic excipient, also enabled solution-mediated cocrystal dissociation in intact tablets. Magnesium stearate, an ionizable but hydrophobic excipient, interacted with the cocrystal to form a hygroscopic product. The interaction is believed to be initiated in the disordered cocrystal-excipient particle interface. In contrast, the cocrystal was stable in the presence of lactose, a neutral excipient with no tendency to sorb water. The risk of unintended cocrystal dissociation can be mitigated by avoiding contact with water both during processing and storage.

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. [ Cryst. Growth Des. 2012 , 12 ( 8 ), 4090 - 4097 ]. The experimentally measured differences in the relative formation enthalpies obtained by integrating the heat flow of each cocrystal against the respective physical mixture were correlated to the physical stability of the cocrystals in the solid state. The relative formation enthalpies of all of the cocrystals studied suggest that the cocrystals are not physically stable at room temperature versus their physical mixtures. To further address relative stability, the cocrystals were slurried in 30% v/v aqueous ethanol, and it was observed that all of the cocrystals revert to GKA within 48 h at room temperature. The slurry experiments are consistent with the relative instability of the cocrystals with respect to their physical mixtures suggested by the DSC results.

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. In particular, the role of the solid-state properties of the salt on the disproportionation reaction is unknown. Herein, various solid forms of a model salt, miconazole mesylate (MM), were evaluated for their tendency to undergo disproportionation when mixed with basic excipients, namely tribasic sodium phosphate dodecahydrate (TSPd) and croscarmellose sodium (CCS), and exposed to moderate relative humidity storage conditions. It was observed that the rate and extent of salt disproportionation were significantly different for the various solid forms of MM. As expected, the amorphous salt was highly susceptible to disproportionation, while the dihydrate salt form was resistant to conversion under the conditions tested. In addition, binary excipient blends of amorphous and anhydrous forms exhibited a reduced extent of disproportionation at a higher relative humidity storage condition. This was due to the competitive kinetics between disproportionation to the free base and conversion to the dihydrate salt form. The results of this study provide important insights into the impact of solid-state form on susceptibility to disproportionation that can be utilized for rationally designing robust pharmaceutical formulations.

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. The proposed cocrystal dissociation mechanism involved water sorption, dissolution of cocrystal and excipient in the sorbed water, proton transfer from oxalic acid to the excipient, and formation of metal salts and caffeine hydrate. In compressed tablets with magnesium stearate, the cocrystal dissociation was readily discerned from the appearance of peaks attributable to caffeine hydrate and stearic acid. Neutral excipients provide an avenue to circumvent the risk of water mediated cocrystal dissociation.

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.

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. For both tablets and API particles, the calculated SAC against MgSt loading afforded a positive linear correlation over the range of MgSt levels examined in this work. On the tablet surface, MgSt was found to be preferentially concentrated at or in the close vicinity of grain boundaries, supporting the idea of compression-driven migration and relocation of MgSt within the tablet. On the particle surface, only discrete aggregates of MgSt were observed, as opposed to the widely accepted phenomenon of the formation of a thin lubricant film around host particles. The selection of proper SEM-EDS operating conditions and the challenges confronted in particle surface mapping are discussed in detail.

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. This work was aimed at elucidating the link between PSP and surface area coverage (SAC) of tablets by MgSt, in relation to some key formulation properties and process parameters, namely MgSt concentration, API loading, API particle size, and mixing conditions. The study was conducted using two model APIs with known high PSPs, tafamidis (TAF) and ertugliflozin-pyroglutamic acid (ERT). Results showed that PSP decreases exponentially with increasing SAC by MgSt. The composition of material stuck to punch face was also explored to better understand the onset of punch sticking and the impact of possible MgSt-effected punch conditioning event.

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. To date, there is an incomplete understanding of key excipient properties influencing salt disproportionation. Specifically, the potential roles of amorphous excipient glass transition temperature and excipient hygroscopicity, if any, on salt disproportionation are still not well understood. Furthermore, the relationship between the compression and the extent of salt disproportionation is an unknown factor. Herein, by utilizing various grades of polyvinylpyrrolidone (PVP), its copolymer, copovidone (PVPVA), and magnesium stearate, a systematic investigation of disproportionation was performed using pioglitazone HCl as a model salt of a weak base. It was observed that there was a poor correlation between excipient hygroscopicity and the rate and extent of disproportionation. However, powder compression into compacts enhanced the rate and extent of disproportionation. This work focused on disproportionation of the salt of a weak base, as basic drugs are more prevalent, however, salts of weak acids may have similar tendencies under relevant conditions. The knowledge gained from this study will help in understanding the role of various excipients with respect to salt disproportionation, paving the way for designing stable salt formulations.

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. Near the phase boundary, minimal conversion between the anhydrous and hydrated forms of caffeine was detected. Using this kinetic data, the phase boundary for these forms was determined to be approximately 67% RH at 10 degrees C, 74.5% RH at 25 degrees C, and 86% RH at 40 degrees C. At each specified temperature, anhydrous caffeine is the thermodynamically stable form below this relative humidity and the hydrate is stable above. The phase boundary data were then fitted using a second order polynomial to determine the stability relationship between anhydrous caffeine and its hydrate at additional temperatures. This approach can be used to rapidly determine the stability relationship for solvatomorphs as well as the relative kinetics of their interconversion. Both of these factors are critical in selecting the development form, designing appropriate stability studies, and developing robust conditions for the preparation and packaging of the API and formulated drug product.

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. This work was aimed at elucidating the key material properties and compaction parameters that influence punch sticking by statistically analyzing punch sticking data of 24 chemically diverse compounds obtained using a set of tooling with removable upper punch tip. Partial least square (PLS) analysis of the data revealed that particle surface area and tablet tensile strength are the most significant factors attributed to punch sticking. Die-wall pressure, ejection force, and take-off force also correlate with sticking, but to a lesser extent.

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. METHODS: Thirty-four healthy subjects received glasdegib 100 mg as three different formulations in the fasted state (diHCl salt or small- or large-particle size maleate formulation); 13 received the large-particle maleate formulation (fed), and 14 concurrently with rabeprazole (fasted); six subjects received glasdegib 50 mg oral solution (fasted). RESULTS: For both new tablet formulations of glasdegib, ratios (Test:Reference) of adjusted geometric means (90% confidence interval) of area under the concentration-time curve from 0 to infinity and maximum plasma concentration were within 80-125% compared with the diHCl formulation (fasted). For the large-particle size formulation (fed), these ratios were 86.3% (81.0-92.0%) and 75.7% (65.3-87.7%), respectively, compared with fasted. When the large-particle maleate formulation was administered concurrently with rabeprazole versus alone (fasted), these ratios were 111.9% (102.8-121.9%) and 87.2% (75.9-100.3%), respectively. The pharmacokinetics of oral solution was similar to the tablet. CONCLUSIONS: The maleate salt-based tablet formulations were bioequivalent to the diHCl tablet formulation. The extent of the observed effect of a high-fat, high-calorie meal or concurrent rabeprazole treatment on glasdegib exposure is not considered clinically meaningful.

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. Fundamentals of structural arrangements in mesophases are compared with several types of disorder in crystalline materials, as well as with short-range ordering in amorphous solids. Main features of the molecular mobility in crystalline mesophases are found to be generally similar to amorphous materials, although some important differences do exist, depending on a particular type of mobility modes involved in relaxation processes. In several case studies reviewed, chemical stability appears to follow the extent of disorder, with the stability of crystalline mesophase found to be intermediate between amorphous (least stable) and crystalline (most stable) materials. Finally, detection of crystalline mesophases during manufacturing of two different types of dosage forms is discussed.

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. A transition temperature (122°C) between the isostructural dehydrate of the nonstoichiometric channel hydrate and the anhydrous polymorph was identified, with the nonstoichiometric channel hydrate being the thermodynamically stable anhydrous form at room temperature (RT). Solid-state storage at a range of RH conditions demonstrated that the nonstoichiometric channel hydrate is also the stable form at RT above an RH of 94%. These results demonstrate that the nonstoichiometric channel hydrate is the stable form at low temperatures, independent of its hydration state. It has been demonstrated that the eutectic-melting method is applicable to the study of thermodynamic stability relationships between anhydrous forms and dehydrated channel hydrates.

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. The LC phase was identified as hexagonal structure by sXRD, with up to 14 high-order reflections detected. The crystalline phase was found to be nonstoichiometric hydrate, based on XRD and water sorption data. The phase diagram of NaDC-water system has been refined based on both results of this study and other reports in literature.

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. Application of the eutectic-melting method enabled accurate determination of the transition temperature (63 degrees C), with Form B as the stable anhydrous form at room temperature. The stability relationships between the anhydrous polymorphs and the monohydrate (Form C) were assessed through exposure of the anhydrous forms to a range of water vapor pressures at room temperature. A phase boundary was identified, with the monohydrate being the thermodynamically stable form above critical water activity values of 0.85 and 0.94 for Forms A and B, respectively. These results provide a better understanding of the form stability as it relates to normal manufacturing and storage conditions for the active pharmaceutical ingredient and drug product.