Effects of Polymers on Cocrystal Growth in a Drug-Drug Coamorphous System: Relations between Glass-to-Crystal Growth and Surface-Enhanced Crystal Growth.

Coamorphous and cocrystal drug delivery systems provide attractive crystal engineering strategies for improving the solubilities, dissolution rates, and oral bioavailabilities of poorly water-soluble drugs. Polymeric additives have often been used to inhibit the unwanted crystallization of amorphous drugs. However, the transformation of a coamorphous phase to a cocrystal phase in the presence of polymers has not been fully elucidated. Herein, we investigated the effects of low concentrations of the polymeric excipients poly(ethylene oxide) (PEO) and poly(vinylpyrrolidone) (PVP) on the growth of carbamazepine-celecoxib (CBZ-CEL) cocrystals from the corresponding coamorphous phase. PEO accelerated the growth rate of the cocrystals by increasing the molecular mobility of the coamorphous system, while PVP had the opposite effect. The coamorphous CBZ-CEL system exhibited two anomalously fast crystal growth modes: glass-to-crystal (GC) growth in the bulk and accelerated crystal growth at the free surface. These two fast growth modes both disappeared after doping with PEO (1-3% w/w) but were retained in the presence of PVP, indicating a potential correlation between the two fast crystal growth modes. We propose that the different effects of PEO and PVP on the crystal growth modes arose from weaker effects of the polymers on cocrystallization at the surface than in the bulk. This work provides a deep understanding of the mechanisms by which polymers influence the cocrystallization kinetics of a multicomponent amorphous phase and highlights the importance of polymer selection in stabilizing coamorphous systems or preparing cocrystals via solid-based methods.

Predicting Colloidal Stability of High-Concentration Monoclonal Antibody Formulations in Common Pharmaceutical Buffers Using Improved Polyethylene Glycol Induced Protein Precipitation Assay.

Colloidal stability is an important consideration when developing high concentration mAb formulations. PEG-induced protein precipitation is a commonly used assay to assess the colloidal stability of protein solutions. However, the practical usefulness and the current theoretical model for this assay have yet to be verified over a large formulation space across multiple mAbs and mAb-based modalities. In the present study, we used PEG-induced protein precipitation assays to evaluate colloidal stability of 3 mAbs in 24 common formulation buffers at 20 and 5 °C. These prediction assays were conducted at low protein concentration (1 mg/mL). We also directly characterized high concentration (100 mg/mL) formulations for cold-induced phase separation, turbidity, and concentratibility by ultrafiltration. This systematic study allowed analysis of the correlation between the results of low concentration assays and the high concentration attributes. The key findings of this study include the following: (1) verification of the usefulness of three different parameters (Cmid, µB, and Tcloud) from PEG-induced protein precipitation assays for ranking colloidal stability of high concentration mAb formulations; (2) a new method to implement PEG-induced protein precipitation assay suitable for high throughput screening with low sample consumption; (3) improvement in the theoretical model for calculating robust thermodynamic parameters of colloidal stability (µB and εB) that are independent of specific experimental settings; (4) systematic evaluation of the effects of pH and buffer salts on colloidal stability of mAbs in common formulation buffers. These findings provide improved theoretical and practical tools for assessing the colloidal stability of mAbs and mAb-based modalities during formulation development.

Atomic-Level Drug Substance and Polymer Interaction in Posaconazole Amorphous Solid Dispersion from Solid-State NMR.

Despite the wide utilization of amorphous solid dispersions (ASDs) for formulating poorly water-soluble drugs, fundamental understanding of the structural basis behind their stability and dissolution behavior is limited. This is largely due to the lack of high-resolution structural tools for investigating multicomponent and amorphous systems in the solid state. In this study, we present what is likely the first publication quantifying the molecular interaction between the drug and polymer in ASDs at an angstrom level by utilizing 19F magic angle spinning (MAS) nuclear magnetic resonance (NMR) techniques. A variant of the 19F-13C rotational-echo and double-resonance (REDOR) technique was developed to quantify interatomic distances by implementing a supercycled symmetry-based recoupling schedule and synchronized simultaneous detection. We successfully deployed the technique to identify "head-to-head" and "head-to-tail" packing of crystalline posaconazole (POSA). To probe molecular interactions between POSA and hypromellose acetate succinate (HPMCAS) in the dispersion, as a major goal of this study, two-dimensional (2D) 1H-19F correlation experiments were performed. The approach facilitated observation of intermolecular hydrogen-to-fluorine contacts between the hydroxyl group of the polymer and the difluorophenyl group of the drug substance. Atomic distance measurement, utilizing the developed 19F-13C REDOR technique, revealed the close proximity of 13COH-19F at 4.3 Å. Numerical modeling analysis suggested a possible hydrogen bonding interaction between the polymer O-H group as an acceptor and POSA fluorine (O-H···F) or difluorophenyl ring (O-H···Ph) as a donor. These 19F MAS NMR techniques, including 2D 19F-1H heteronuclear correlation and 19F-13C atomic distance measurement, may shed light on the nature (i.e., type and strength) of drug-polymer interactions in ASDs and offer a new high-resolution analytical protocol for probing the microstructure of amorphous pharmaceutical materials.

In situ solid-state NMR characterization of pharmaceutical materials: An example of drug-polymer thermal mixing.

Pharmaceutical amorphous solid dispersions, a multicomponent system prepared by dispersing drug substances into polymeric matrix via thermal and mechanical processes, represent a major platform to deliver the poorly water-soluble drug. Microscopic properties of drug-polymer contacts play mechanistic roles in manipulating long-term physical stability as well as dissolution profiles. Although solid-state nuclear magnetic resonance has been utilized as an indispensable tool to probe structural details, previous studies are limited to ex situ characterizations. Our work provides likely the first documented example to investigate comelting of ketoconazole and polyacrylic acid, as a model system, in an in situ manner. Their physical mixture is melted and mixed in the solid-state nuclear magnetic resonance rotor under magic angle spinning at up to approximately 400 K. Critical structural events of molecular miscibility and interaction have been successfully identified. These results design and evaluate the instrumental and experimental protocols for real-time characterizations of the comelting of pharmaceutical materials.

Understanding Compression-Induced Amorphization of Crystalline Posaconazole.

Process-induced phase transformations (PIPTs) of active pharmaceutical ingredients (APIs) can alter APIs' physicochemical properties and impact performance of pharmaceutical drug products. In this study, we investigated compression-induced amorphization of crystalline posaconazole (POSA), where the impact of mechanical stresses and excipients on amorphization were explored. 19F solid-state NMR (ssNMR) was utilized to detect and quantify amorphous content in the compressed tablets, and finite element analysis (FEA) was conducted to understand stress distributions in the compression process. Both applied macroscopic axial stress and shear stress were found to be important to amorphization of crystalline POSA. Punch velocity, an important compression process parameter, had negligible effect on amorphization up to 100 mm/s. Two diluents, microcrystalline cellulose (MCC) and dibasic calcium phosphate anhydrous (DCPA), and one lubricant, magnesium stearate (MgSt), were evaluated for their impact on amorphization in this study. It was found that both MCC and DCPA significantly enhanced amorphization of POSA at a low drug loading (5% w/w). The 1% (w/w) blended lubricant effectively reduced the amorphous content in MCC-POSA tablets; however, it had minimal effect on either neat POSA or DCPA-POSA tablets. Drug loading, or excipient concentration, was demonstrated to have a significant impact on the extent of amorphization. These observed excipient effects support the important role of interparticulate stresses in amorphization of crystalline POSA.

Surface Enrichment and Depletion of the Active Ingredient in Spray Dried Amorphous Solid Dispersions.

PURPOSE: To study the effects of physicochemical properties of drug and polymer, as well as the drug-polymer interactions, on the surface composition of SDDs. METHODS: Ethanol solutions containing a model drug (IMC, NMP or FCZ) and a model polymer (PVPK12, PVPK30 or PVP-VA) were spray dried, and the surface composition of SDDs was analyzed by XPS. The surface tensions of pure components and their solutions were measured using Wilhelmy plate and/or calculated using ACD/Labs. NMR and DLS were used to obtain the diffusion coefficients of IMC, NMP, PVPK12 and PVPK30 in solvents. Flory-Huggins interaction parameters for selected drug-polymer pairs were obtained using a melting point depression method. RESULTS: Significant surface enrichment or depletion of the drug was observed in SDDs depending on the particular drug-polymer combination. With PVP as the dispersion polymer, IMC and NMP were surface enriched; whereas FCZ, a hydrophilic drug, was surface depleted. With increasing PVP molecular weight, the surface drug concentration increased, and the effect was greater in the NMP/PVP and FCZ/PVP systems than in the IMC/PVP system where strong drug-polymer interaction existed. Changing the polymer from PVP to PVP-VA reduced the surface concentration of the drug. CONCLUSIONS: The surface concentration of a SDD can be significantly different from the bulk concentration. The main results of this work are consistent with the notion that the relative surface tensions control surface enrichment or depletion. Besides, the relative diffusion rates of the components and the strength of their interactions may also affect the surface composition of the SDDs.

Rheology Guided Rational Selection of Processing Temperature To Prepare Copovidone-Nifedipine Amorphous Solid Dispersions via Hot Melt Extrusion (HME).

The production of amorphous solid dispersions via hot melt extrusion (HME) relies on elevated temperature and prolonged residence time, which can result in potential degradation and decomposition of thermally sensitive components. Herein, the rheological properties of a physical mixture of polymer and an active pharmaceutical ingredient (API) were utilized to guide the selection of appropriate HME processing temperature. In the currently studied copovidone-nifedipine system, a critical temperature, which is substantially lower (∼13 °C) than the melting point of crystalline API, was captured during a temperature ramp examination and regarded as the critical point at which the API could molecularly dissolve into the polymer. Based on the identification of this critical point, various solid dispersions were prepared by HME processing below, at, and above the critical temperature (both below and above the melting temperature (Tm) of crystalline API). In addition, the resultant extrudates along with two control solid dispersions prepared by physical mixing and cryogenic milling were assessed by X-ray diffraction, differential scanning calorimetry, hot stage microscopy, rheology, and solid-state NMR. Physicochemical properties of resultant solid dispersions indicated that the identified critical temperature is sufficient for the polymer-API system to reach a molecular-level mixing, manifested by the transparent and smooth appearance of extrudates, the absence of API crystalline diffraction and melting peaks, dramatically decreased rheological properties, and significantly improved polymer-API miscibility. Once the critical temperature has been achieved, further raising the processing temperature only results in limited improvement of API dispersion, reflected by slightly reduced storage modulus and complex viscosity and limited improvement in miscibility.

Variables Impacting Silicone Oil Migration and Biologics in Prefilled Syringes.

Prefilled syringes (PFS) as a primary container for parenteral drug products offer significant advantages, such as fast delivery time, ease of self-administration and fewer dosing errors. Despite the benefits that PFS can provide to patients, the silicone oil pre-coated on the glass barrels has shown migration into the drug product, which can impact particle formation and syringe functionality. Health authorities have urged product developers to better understand the susceptibility of drug products to particle formation in PFS due to silicone oil. In the market, there are multiple syringe sources provided by various PFS suppliers. Due to current supply chain shortages and procurement preferences for commercial products, the PFS source may change in the middle of development. Additionally, health authorities require establishing source duality. Therefore, it is crucial to understand how different syringe sources and formulation compositions impact the drug product quality. Here, several design of experiments (DOE) are executed that focus on the risk of silicone oil migration induced by syringe sources, surfactants, protein types, stress, etc. We utilized Resonant Mass Measurement (RMM) and Micro Flow Imaging (MFI) to characterize silicone oil and proteinaceous particle distribution in both micron and submicron size ranges, as well as ICP-MS to quantify silicon content. The protein aggregation and PFS functionality were also monitored in the stability study. The results show that silicone oil migration is impacted more by syringe source, siliconization process and surfactant (type & concentration). The break loose force and extrusion force across all syringe sources increase significantly as protein concentration and storage temperature increase. Protein stability is found to be impacted by its molecular properties and is less impacted by the presence of silicone oil, which is the same inference drawn in other literatures. A detailed evaluation described in this paper enables a thorough and optimal selection of primary container closure and de-risks the impact of silicone oil on drug product stability.

Coating Polyelectrolyte Multilayers Loaded with Quercetin on Titanium Surfaces by Layer-By-Layer Assembly Technique to Improve Surface Osteogenesis Under Osteoporotic Condition.

Titanium (Ti) and its alloy implants are widely used in the field of orthopedics, and osteoporosis is an important reason for implantation failure. This study aimed to establish a quercetin (QTN) controlled release system on the surface of titanium implants and to study its effects on osteogenesis and osseointegration on the surface of implants. Polyethylenimine (PEI) was first immobilized on a titanium substrate as the base layer, and then, hyaluronic acid/chitosan-quercetin (HA/CS-QTN) multilayer films were assembled on the PEI layer by a self-assembly technique. Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM) and contact angle measurements were used to characterize and analyze the samples. The release characteristics of QTN were studied by release assays. The osteogenic ability of the samples was evaluated by experiments on an osteoporosis rat model and MC3T3-E1 cells. The FTIR, SEM, and contact angle measurements all showed that the PEI substrate layer and HA/CS-QTN multilayer film were successfully immobilized on the titanium matrix. The drug release test showed the successful establishment of a QTN controlled release system. The in vitro results showed that osteoblasts exhibited higher adhesion, proliferation and differentiation ability on the coated titanium matrix than on the pure titanium surface. In addition, the in vivo results showed that the HA/CS-QTN coating significantly increased the new bone mass around the implant. By depositing a PEI matrix layer and HA/CS-QTN multilayer films on titanium implants, a controlled release system of QTN was established, which improved implant surface osseointegration under osteoporotic conditions. This study proposes a new implant therapy strategy for patients with osteoporosis.

Stereocomplex Prodrugs of Oligo(lactic acid) n-Gemcitabine in Poly(ethylene glycol)- block-poly(d,l-lactic acid) Micelles for Improved Physical Stability and Enhanced Antitumor Efficacy.

Herein we demonstrate the formation of stereocomplex prodrugs of oligo(l-lactic acid) n-gemcitabine (o(LLA) n-GEM) and oligo(d-lactic acid) n-gemcitabine (o(DLA) n-GEM) for stable incorporation in poly(ethylene glycol)- block-poly(d,l-lactic acid) (PEG- b-PLA) micelles. O(LLA) n or o(DLA) n was attached at the amino group (4-( N)) of GEM via an amide linkage. When n = 10, a 1:1 mixture of o(LLA)10-GEM and o(DLA)10-GEM (o(L+DLA)10-GEM) was able to form a stereocomplex with a distinctive crystalline pattern. Degradation of o(L+DLA)10-GEM was driven by both backbiting conversion and esterase contribution, generating primarily o(L+DLA)1-GEM and GEM. O(L+DLA)10-GEM stably loaded in PEG- b-PLA micelles in the size range of 140-200 nm with an unexpected elongated morphology. The resulting micelles showed improved physical stability in aqueous media and inhibited backbiting conversion of o(L+DLA)10-GEM within micelles. Release of o(L+DLA)10-GEM from micelles was relatively slow, with a t1/2 at ca. 60 h. Furthermore, weekly administration of o(L+DLA)10-GEM micelles i.v. displayed potent antitumor activity in an A549 human non-small-cell lung carcinoma xenograft model. Thus, stereocomplexation of isotactic o(LLA) n and o(DLA) n acts as a potential prodrug strategy for improved stability and sustained drug release in PEG- b-PLA micelles.