Assessing Photostability of mAb Formulations In Situ Using Light-Coupled NMR Spectroscopy.

Biopharmaceuticals, such as monoclonal antibodies (mAbs), need to maintain their chemical and physical stability in formulations throughout their lifecycle. It is known that exposure of mAbs to light, particularly UV, triggers chemical and physical degradation, which can be exacerbated by trace amounts of photosensitizers in the formulation. Although routine assessments of degradation following defined UV dosages are performed, there is a fundamental lack of understanding regarding the intermediates, transient reactive species, and radicals formed during illumination, as well as their lifetimes and immediate impact post-illumination. In this study, we used light-coupled NMR spectroscopy to monitor in situ live spectral changes in sealed samples during and after UV-A illumination of different formulations of four mAbs without added photosensitizers. We observed a complex evolution of spectra, reflecting the appearance within minutes of transient radicals during illumination and persisting for minutes to tens of minutes after the light was switched off. Both mAb and excipient signals were strongly affected by illumination, with some exhibiting fast irreversible photodegradation and others exhibiting partial recovery in the dark. These effects varied depending on the mAb and the presence of excipients, such as polysorbate 80 (PS80) and methionine. Complementary ex situ high-performance size-exclusion chromatography analysis of the same formulations post-UV exposure in the chamber revealed significant loss of purity, confirming formulation-dependent degradation. Both approaches suggested the presence of degradation processes initiated by light but continuing in the dark. Further studies on photoreaction intermediates and transient reactive species may help mitigate the impact of light on biopharmaceutical degradation.

Prediction of Degradation Profiles for Various Sartans under Solvent-Free Mechanochemical Conditions.

For the approval of a drug, the stability data must be submitted to regulatory authorities. Such analyses are often time-consuming and cost-intensive. Forced degradation studies are mainly carried out under harsh conditions in the dissolved state, often leading to extraneous degradation profiles for a solid drug. Oxidative mechanochemical degradation offers the possibility of generating realistic degradation profiles. In this study, a sustainable mechanochemical procedure is presented for the degradation of five active pharmaceutical ingredients (APIs) from the sartan family: losartan potassium, irbesartan, valsartan, olmesartan medoxomil, and telmisartan. High-resolution mass spectrometry enabled the detection of impurities already present in untreated APIs and allowed the elucidation of degradation products. Significant degradation profiles could already be obtained after 15-60 min of ball milling time. Many of the identified degradation products are described in the literature and pharmacopoeias, emphasizing the significance of our results and the applicability of this approach to predict degradation profiles for drugs in the solid state.

Acidic solvent improves cisplatin action in in-vitro.

As cisplatin is one of the most broadly used chemotherapeutics, it is widely tested in vitro & in vivo assays, involving attempts to better understand its mechanism of action, develop strategies to mitigate its toxicity, or develop new drug combinations. Presently, for in vitro assays, dissolving cisplatin in dimethyl sulfoxide (DMSO) is discouraged due to its significant reduction in drug activity, Alternatively, inorganic solvents like normal saline (NS) are recommended. However, this approach is still problematic, including 1) instability of cisplatin in NS, 2) limited solubility, 3) the need to avoid long-term storage at -80 °C (or -20 °C) after dissolving, and 4) complications when combining with other DMSO-solubilized compounds. Here, we report a DMSO-HCl mixture as an alternative solvent to address these challenges. Cisplatin in DMSO-HCl not only retains comparable drug activity to cisplatin in NS but also exhibits increased stability over an extended period. Our brief report sheds light on cisplatin action, providing insights to aid in cancer research in vitro.

Breaking barriers in pharmaceutical analysis: Streamlined UV spectrometric quantification and stability profiling of haloperidol and methylparaben in liquid formulations.

This study aims to quantify haloperidol and methylparaben in a liquid pharmaceutical formulation (2 mg/ml) using UV spectrometry and the simultaneous equations method. Additionally, we explored the stability of haloperidol under various stress conditions. The UV analysis revealed maximum absorption peaks at 248 nm for haloperidol and 256 nm for methylparaben, using a 1 % (v/v) lactic acid solution as the solvent. Method validation, conducted according to ICH guidelines, affirmed the method's reliability, showing excellent results in terms of linearity, precision, accuracy, and sensitivity. The method allows direct application to finished products, enabling simultaneous quantification without extractions. Its simplicity, speed, and cost-effectiveness make it ideal for routine controls in pharmaceutical industry haloperidol solution analyses. The method extends to monitoring forced degradation, indicating photolytic and hydrolytic degradation under acidic and basic conditions, while affirming thermal and oxidative stability. This proposed UV spectrometric method serves as a compelling alternative to pharmacopeia-recommended techniques, simplifying simultaneous determination of the active ingredient and preservative. This streamlines analysis, reducing time and costs. Additionally, it proves valuable in small industries lacking sophisticated instrumentation, offering insights into active ingredient behavior during forced degradation.

Effect of Annealing on Visible-Bubble Formation and Stability Profiles of Freeze-Dried High Concentration Omalizumab Formulations.

In the clinical application of freeze-dried highly concentrated omalizumab formulations, extensive visible bubbles (VBs) can be generated and remain for a long period of time in the reconstitution process, which greatly reduces the clinical use efficiency. It is necessary to understand the forming and breaking mechanism of VBs in the reconstitution process, which is a key factor for efficient and safe administration of biopharmaceutical injection. The effects of different thermal treatments on the volume of VBs and stability of omalizumab, mAb-1, and mAb-2 were investigated. The internal microvoids of the cake were characterized by scanning electron microscopy and mercury intrusion porosimetry. Electron paramagnetic resonance was applied to obtain the molecular mobility of the protein during annealing. A large number of VBs were generated in the reconstitution process of unannealed omalizumab and remained for a long period of time. When annealing steps were added, the volume of VBs was dramatically reduced. When annealed at an aggressive temperature (i.e., -6 °C), although the volume of VBs decreased, the aggregation and acidic species increased significantly. Thus, our observations highlight the importance of setting an additional annealing step with a suitable temperature, which contributes to reducing the VBs while maintaining the stability of the high concentration freeze-dried protein formulation.

Predicting Long-Term Stability of an Oral Delivered Antibody Drug Product with Accelerated Stability Assessment Program Modeling.

The oral delivery of protein therapeutics offers numerous advantages for patients but also presents significant challenges in terms of development. Currently, there is limited knowledge available regarding the stability and shelf life of orally delivered protein therapeutics. In this study, a comprehensive assessment of the stability of an orally delivered solid dosage variable domain of heavy-chain antibody (VHH antibody) drug product was conducted. Four stability related quality attributes that undergo change as a result of thermal and humidity stress were identified. Subsequently, these attributes were modeled using an accelerated stability approach facilitated by ASAPprime software. To the best of our knowledge, this is the first time that this approach has been reported for an antibody drug product. We observed overall good model quality and accurate predictions regarding the protein stability during storage. Notably, we discovered that protein aggregation, formed through a degradation pathway, requires additional adjustments to the modeling method. In summary, the ASAP approach demonstrated promising results in predicting the stability of this complex solid-state protein formulation. This study sheds light on the stability and shelf life of orally delivered protein therapeutics, addressing an important knowledge gap in the field.

Preparation and Characterization of a Rifampicin Coamorphous Material with Tromethamine Coformer: An Experimental-Theoretical Study.

Rifampicin (RIF) is an antibiotic used to treat tuberculosis and leprosy. Even though RIF is a market-available drug, it has a low aqueous solubility, hindering its bioavailability. Among the strategies for bioavailability improvement of poorly soluble drugs, coamorphous systems have been revealed as an alternative in the increase of the aqueous solubility of drug systems and at the same time also increasing the amorphous state stability and dissolution rate when compared with the neat drug. In this work, a new coamorphous form from RIF and tromethamine (TRIS) was synthesized by slow evaporation. Structural, electronic, and thermodynamic properties and solvation effects, as well as drug-coformer intermolecular interactions, were studied through density functional theory (DFT) calculations. Powder X-ray diffraction (PXRD) data allowed us to verify the formation of a new coamorphous. In addition, the DFT study indicates a possible intermolecular interaction by hydrogen bonds between the available amino and carbonyl groups of RIF and the hydroxyl and amino groups of TRIS. The theoretical spectra obtained are in good agreement with the experimental data, suggesting the main interactions occurring in the formation of the coamorphous system. PXRD was used to study the physical stability of the coamorphous system under accelerated ICH conditions (40 °C and 75% RH), indicating that the material remained in an amorphous state up to 180 days. The thermogravimetry result of this material showed a good thermal stability up to 153 °C, and differential scanning calorimetry showed that the glass temperature (Tg) was at 70.0 °C. Solubility studies demonstrated an increase in the solubility of RIF by 5.5-fold when compared with its crystalline counterpart. Therefore, this new material presents critical parameters that can be considered in the development of new coamorphous formulations.

Microscopic Cracks Modulate Nucleation and Solid-State Crystallization Tendency of Amorphous Celecoxib.

Drugs have been classified as fast, moderate, and poor crystallizers based on their inherent solid-state crystallization tendency. Differential scanning calorimetry-based heat-cool-heat protocol serves as a valuable tool to define the solid-state crystallization tendency. This classification helps in the development of strategies for stabilizing amorphous drugs. However, microscopic characteristics of the samples were generally overlooked during these experiments. In the present study, we evaluated the influence of microscopic cracks on the crystallization tendency of a poorly water-soluble model drug, celecoxib. Cracks developed in the temperature range of 0-10 °C during the cooling cycle triggered the subsequent crystallization of the amorphous phase. Nanoindentation study suggested minimal differences in mechanical properties between samples, although the cracked sample showed relatively inhomogeneous mechanical properties. Nuclei nourishment experiments suggested crack-assisted nucleation, which was supported by Raman data that revealed subtle changes in intermolecular interactions between cracked and uncracked samples. Celecoxib has been generally classified as class II, i.e., a drug with moderate crystallization tendency. Interestingly, classification of amorphous celecoxib may change depending on the presence or absence of cracks in the amorphous sample. Hence, subtle events such as microscopic cracks should be given due consideration while defining the solid-state crystallization tendency of drugs.

Clinical and Preclinical Methods of Heat-Stabilization of Human Vaccines.

Vaccines have historically faced challenges regarding stability, especially in regions lacking a robust cold chain infrastructure. This review delves into established and emergent techniques to improve the thermostability of vaccines. We discuss the widely practiced lyophilization method, effectively transforming liquid vaccine formulations into a solid powdered state, enhancing storage and transportation ability. However, potential protein denaturation during lyophilization necessitates alternative stabilization methods. Cryoprotectants, namely, starch and sugar molecules, have shown promise in protecting vaccine antigens and adjuvants from denaturation and augmenting the stability of biologics during freeze-drying. Biomineralization, a less studied yet innovative approach, utilizes inorganic or organic-inorganic hybrids to encapsulate biological components of vaccines with a particular emphasis on metal-organic coordination polymers. Encapsulation in organic matrices to form particles or microneedles have also been studied in the context of vaccine thermostability, showing some ability to store outside the cold-chain. Unfortunately, few of these techniques have advanced to clinical trials that evaluate differences in storage conditions. Nonetheless, early trials suggest that alternative storage techniques are viable and emphasize the need for more comprehensive studies. This review underscores the pressing need for heat-stable vaccines, especially in light of the increasing global distribution challenges. Combining traditional methods with novel approaches holds promise for the future adaptability of vaccine distribution and use.

Simultaneous Water Sorption and Crystallization in ASDs 1: Stability Studies Lasting for Two Years.

One way to increase the slow dissolution rate and the associated low bioavailability of newly developed active pharmaceutical ingredients (APIs) is to dissolve the API in a polymer, leading to a so-called amorphous solid dispersion (ASD). However, APIs are often supersaturated in ASDs and thus tend to crystallize during storage. The kinetics of the crystallization process is determined by the amount of water the ASD absorbs during storage at relative humidity (RH), storage temperature, polymer type, and the drug load of the ASD. Here, the crystallization kinetics and shelf life of spray-dried ASDs were investigated for ASDs consisting of nifedipine (NIF) or celecoxib (CCX) as the APIs and of poly(vinylpyrrolidone-co-vinyl acetate) or hydroxypropyl methylcellulose acetate succinate as polymers. Samples were stored over 2 years at different RHs covering conditions above and below the glass transition of the wet ASDs. Crystallization kinetics and onset time of the crystallization were qualitatively studied by using powder X-ray diffraction and microscopic inspection and were quantitatively determined by using differential scanning calorimetry. It was found that the NIF ASDs crystallize much faster than CCX ASDs at the same drug load and at the same storage conditions due to both higher supersaturation and higher molecular mobility in the NIF ASDs. Experimental data on crystallization kinetics were correlated using the Johnson-Mehl-Avrami-Kolmogorov equation. A detailed thermodynamic and kinetic modeling will be performed in Part 2 of this paper series.

Toward the Establishment of a Harmonized Physicochemical Profiling Platform for Therapeutic Oligonucleotides: A Case Study for Aptamers Where the Higher-Order Structure Influences Physical Properties.

Oligonucleotides are short nucleic acids that serve as one of the most promising classes of drug modality. However, attempts to establish a physicochemical evaluation platform of oligonucleotides for acquiring a comprehensive view of their properties have been limited. As the chemical stability and the efficacy as well as the solution properties at a high concentration should be related to their higher-order structure and intra-/intermolecular interactions, their detailed understanding enables effective formulation development. Here, the higher-order structure and the thermodynamic stability of the thrombin-binding aptamer (TBA) and four modified TBAs, which have similar sequences but were expected to have different higher-order structures, were evaluated using ultraviolet spectroscopy (UV), circular dichroism (CD), differential scanning calorimetry (DSC), and nuclear magnetic resonance (NMR). Then, the relationship between the higher-order structure and the solution properties including solubility, viscosity, and stability was investigated. The impact of the higher-order structure on the antithrombin activity was also confirmed. The higher-order structure and intra-/intermolecular interactions of the oligonucleotides were affected by types of buffers because of different potassium concentrations, which are crucial for the formation of the G-quadruplex structure. Consequently, solution properties, such as solubility and viscosity, chemical stability, and antithrombin activity, were also influenced. Each instrumental analysis had a complemental role in investigating the higher-order structure of TBA and modified TBAs. The utility of each physicochemical characterization method during the preclinical developmental stages is also discussed.

A Model Study to Assess Fibrillation and Product Stability to Support Peptide Drug Design.

The fibrillation of therapeutic peptides can present significant quality concerns and poses challenges for manufacturing and storage. A fundamental understanding of the mechanisms of fibrillation is critical for the rational design of fibrillation-resistant peptide drugs and can accelerate product development by guiding the selection of solution-stable candidates and formulations. The studies reported here investigated the effects of structural modifications on the fibrillation of a 29-residue peptide (PepA) and two sequence modified variants (PepB, PepC). The C-terminus of PepA was amidated, whereas both PepB and PepC retained the carboxylate, and Ser16 in PepA and PepB was substituted with a helix-stabilizing residue, α-aminoisobutyric acid (Aib), in PepC. In thermal denaturation studies by far-UV CD spectroscopy and fibrillation kinetic studies by fluorescence and turbidity measurements, PepA and PepB showed heat-induced conformational changes and were found to form fibrils, whereas PepC did not fibrillate and showed only minor changes in the CD signal. Pulsed hydrogen-deuterium exchange mass spectrometry (HDX-MS) showed a high degree of protection from HD exchange in mature PepA fibrils and its proteolytic fragments, indicating that most of the sequence had been incorporated into the fibril structure and occurred nearly simultaneously throughout the sequence. The effects of the net peptide charge and formulation pH on fibrillation kinetics were investigated. In real-time stability studies of two formulations of PepA at pH's 7.4 and 8.0, analytical methods detected significant changes in the stability of the formulations at different time points during the study, which were not observed during accelerated studies. Additionally, PepA samples were withdrawn from real-time stability and subjected to additional stress (40 °C, continuous shaking) to induce fibrillation; an approach that successfully amplified oligomers or prefibrillar species previously undetected in a thioflavin T assay. Taken together, these studies present an approach to differentiate and characterize fibrillation risk in structurally related peptides under accelerated and real-time conditions, providing a model for rapid, iterative structural design to optimize the stability of therapeutic peptides.

Exploring Salts of Memantine with Inorganic Anions: From Polymorphism and Solid-State Transitions to Potential for Drug Formulations.

This study examines pharmaceutically acceptable inorganic salts of memantine, specifically focusing on hydrogen sulfate, sulfate, and dihydrogen phosphate salts, with the aim of finding alternatives to the commonly used chloride salt in the treatment of Alzheimer's disease. Through comprehensive solid-state characterization, including powder X-ray diffraction, thermal analysis, and solubility testing, we unveil complex polymorphic behaviors, reversible solid-state transitions, and significant differences in solubility and stability among the salts. Notably, the hydrogen sulfate salt emerges as a promising candidate for drug formulations, offering improved solubility, nonhygroscopic nature, and favorable morphological characteristics compared to the existing chloride salt. This work establishes a foundation for further investigation into memantine salts as potential therapeutics with improved efficacy.

Predicting the Long-Term Stability of Biologics with Short-Term Data.

Understanding the long-term stability of biologics is crucial to ensure safe, effective, and cost-efficient life-saving therapeutics. Current industry and regulatory practices require arduous real-time data collection over three years; thus, reducing this bottleneck while still ensuring product quality would enhance the speed of medicine to patients. We developed a parallel-pathway kinetic model, combined with Monte Carlo simulations for prediction intervals, to predict the long-term (2+ years) stability of biotherapeutic critical quality attributes (aggregates, fragments, charge variants, purity, and potency) with short-term (3-6 months) data from intended, accelerated, and stressed temperatures. We rigorously validated the model with 18 biotherapeutic drug products, composed of IgG1 and IgG4 monoclonal antibodies, antibody-drug conjugates, dual protein coformulations, and a fusion protein, including high concentration (≥100 mg/mL) formulations, in liquid and lyophilized presentations. For each drug product, we accurately predicted the long-term trends of multiple quality attributes using just 6 months of data. Further, we demonstrated superior stability prediction via our methods compared with industry-standard linear regression methods. The robust and repeatable results of this work across an unprecedented suite of 18 biotherapeutic compounds suggest that kinetic models with Monte Carlo simulation can predict the long-term stability of biologics with short-term data.

Modeling the Structure of Ketoprofen-Poly(vinylpyrrolidone) Amorphous Solid Dispersions with Empirical Potential Structure Refinements of X-ray Scattering Data.

The metastability of amorphous formulations poses barriers to their safe and widespread commercialization. The propensity of amorphous solid dispersions (ASDs) to crystallize is directly linked to their molecular structure. Amorphous structures are inherently complex and thus difficult to fully characterize by experiments, which makes structural simulations an attractive route for investigating which structural characteristics correlate with ASD stability. In this study, we use empirical potential structure refinement (EPSR) to create molecular models of ketoprofen-poly(vinylpyrrolidone) (KTP/PVP) ASDs with 0-75 wt % drug loading. The EPSR technique uses X-ray total scattering measurements as constraints, yielding models that are consistent with the X-ray data. We perform several simulations to assess the sensitivity of the EPSR approach to input parameters such as intramolecular bond rotations, PVP molecule length, and PVP tacticity. Even at low drug loading (25 wt %), ∼40% of KTP molecules participate in KTP-KTP hydrogen bonding. The extent of KTP-PVP hydrogen bonding does not decrease significantly at higher drug loadings. However, the models' relative uncertainties are too large to conclude whether ASDs' lower stabilities at high drug loadings are due to changes in drug-excipient hydrogen bonding or a decrease in steric hindrance of KTP molecules. This study illustrates how EPSR, combined with total scattering measurements, can be a powerful tool for investigating structural characteristics in amorphous formulations and developing ASDs with improved stability.

Predicting the Stability of Formulations Containing Lyophilized Human Serum Albumin and Sucrose/Trehalose Using Solid-State NMR Spectroscopy.

Stabilization of proteins by disaccharides in lyophilized formulations depends on the interactions between the protein and the disaccharide (system homogeneity) and the sufficiently low mobility of the system. Human serum albumin (HSA) was lyophilized with disaccharides (sucrose and/or trehalose) in different relative concentrations. Solid-state nuclear magnetic resonance (ssNMR) spectroscopy 1H T1 and 1H T1ρ relaxation times were measured to determine the homogeneity of the lyophilized systems on 20-50 and 1-3 nm domains, respectively, with 1H T1 relaxation times also being used to determine the ß-relaxation rate. HSA/sucrose systems had longer 1H T1 relaxation times and were slightly more stable than HSA/trehalose systems in almost all cases shown. HSA/sucrose/trehalose systems have 1H T1 relaxation times between the HSA/sucrose and HSA/trehalose systems and did not result in a more stable system compared with binary systems. Inhomogeneity was evident in a sample containing relative concentrations of 10% HSA and 90% trehalose, suggesting trehalose crystallization during lyophilization. Under these stability conditions and with these ssNMR acquisition parameters, a 1H T1 relaxation time below 1.5 s correlated with an unstable sample, regardless of the disaccharide(s) used.

Simultaneous Water Sorption and Crystallization in ASDs 2: Modeling Long-Term Stabilities.

The physical stability of amorphous solid dispersions (ASDs) is a major topic in the formulation research of oral dosage forms. To minimize the effort of investigating the long-term stability using cost- and time-consuming experiments, we developed a thermodynamic and kinetic modeling framework to predict and understand the crystallization kinetics of ASDs during long-term storage below the glass transition. Since crystallization of the active phrarmaceutical ingredients (APIs) in ASDs largely depends on the amount of water absorbed by the ASDs, water-sorption kinetics and API-crystallization kinetics were considered simultaneously. The developed modeling approach allows prediction of the time evolution of viscosity, supersaturation, and crystallinity as a function of drug load, relative humidity, and temperature. It was applied and evaluated against two-year-lasting crystallization experiments of ASDs containing nifedipine and copovidone or HPMCAS measured in part I of this work. We could show that the proposed modeling approach is able to describe the interplay between water sorption and API crystallization and to predict long-term stabilities of ASDs just based on short-term measurements. Most importantly, it enables explaining and understanding the reasons for different and sometimes even unexpected crystallization behaviors of ASDs.

Unveiling the Molecular Dynamics, Anticancer Activity, and Stability of Spearmint Oil Nanoemulsions with Triglycerides.

Although spearmint oil (SMO) has various pharmacological properties, especially for cancer treatment, its low water solubility results in poor bioavailability. This limits its application as a medicine. One possible solution is to the use of SMO in the form of nanoemulsion, which has already been shown to have anticancer effects. However, the mechanism of SMO nanoemulsion formation remains unclear. The objective of this study was to use molecular dynamics (MD) for clarifying the formation of SMO nanoemulsion with triglycerides (trilaurin, tripalmitin, and triolein) and Cremophor RH40 (PCO40). Nanoemulsions with different SMO:triglyceride ratios and triglyceride types were prepared and analyzed for anticancer activity, droplet size, droplet morphology, and stability. Despite switching the type of carrier oil, SMO nanoemulsions retained strong anticancer effects. A ratio of 80SMO:20triglycerides produced the smallest droplets (<100 nm) and exhibited excellent physical stability after a temperature cycling test. MD simulations showed that polyoxyethylenes of PCO40 are located at the water interface, stabilizing the emulsion structure in an egglike layer. Droplet size correlated with triglyceride concentration, which was consistent with the experimental findings. Decreasing triglyceride content, except for the 90SMO:10triglyceride ratio, led to a decrease in droplet sizes. Hydrogen bond analysis identified interactions between triglyceride-PCO40 and carvone-PCO40. Geometry analysis showed PCO40 had an "L-like" shape, which maximizes the hydrophilic interfaces. These findings highlight the value of MD simulations in understanding the formation mechanism of SMO and triglyceride nanoemulsions. In addition, it might also be beneficial to use MD simulations before the experiment to select the potential composition for nanoemulsions, especially essential oil nanoemulsions.

Understanding the Roles of Excipients in Moisture Management in Solid Dosage Forms.

Excipients are ubiquitous in pharmaceutical products, and often, they can also play a critical role in maintaining product quality. For a product containing a moisture-sensitive drug, moisture can be deleterious to the product stability during storage. Therefore, using excipients that interact with moisture in situ can potentially alleviate product stability issues. In this study, the interactive behavior of starch with moisture was augmented by coprocessing maize starch with sodium chloride (NaCl) or magnesium nitrate hexahydrate [Mg(NO3)2·6H2O] at different concentrations (5 and 10%, w/w). The effect of the formulation on drug stability was assessed through the degradation of acetylsalicylic acid, which was used as the model drug. The results showed that coprocessing of the starch with either NaCl or Mg(NO3)2·6H2O impacted the number of water molecule binding sites on the starch and how the sorbed moisture was distributed. The coprocessed excipients also resulted in lower drug degradation and lesser changes in tablet tensile strength during post-compaction storage. However, corresponding tablet formulations containing physical mixtures of starch and salts did not yield promising outcomes. This study demonstrated the advantageous concomitant use of common excipients by coprocessing to synergistically mitigate the adverse effects of moisture and promote product stability when formulating a moisture-sensitive drug. In addition, the findings could help to improve the understanding of moisture-excipient interactions and allow for the judicious choice of excipients when designing formulations containing moisture-sensitive drugs.

Colyophilized Sugar-Polymer Dispersions for Enhanced Processing and Storage Stability.

Sucrose and trehalose pharmaceutical excipients are employed to stabilize protein therapeutics in a dried state. The mechanism of therapeutic protein stabilization is dependent on the sugars being present in an amorphous solid-state. Colyophilization of sugars with high glass transition polymers, polyvinylpyrrolidone (PVP), and poly(vinylpyrrolidone vinyl acetate) (PVPVA), enhances amorphous sugar stability. This study investigates the stability of colyophilized sugar-polymer systems in the frozen solution state, dried state postlyophilization, and upon exposure to elevated humidity. Binary systems of sucrose or trehalose with PVP or PVPVA were lyophilized with sugar/polymer ratios ranging from 2:8 to 8:2. Frozen sugar-PVPVA solutions exhibited a higher glass transition temperature of the maximally freeze-concentrated amorphous phase (Tg') compared to sugar-PVP solutions, despite the glass transition temperature (Tg) of PVPVA being lower than PVP. Tg values of all colyophilized systems were in a similar temperature range irrespective of polymer type. Greater hydrogen bonding between sugars and PVP and the lower hygroscopicity of PVPVA influenced polymer antiplasticization effects and the plasticization effects of residual water. Plasticization due to water sorption was investigated in a dynamic vapor sorption humidity ramping experiment. Lyophilized sucrose systems exhibited increased amorphous stability compared to trehalose upon exposure to the humidity. Recrystallization of trehalose was observed and stabilized by polymer addition. Lower concentrations of PVP inhibited trehalose recrystallization compared to PVPVA. These stabilizing effects were attributed to the increased hydrogen bonding between trehalose and PVP compared to trehalose and PVPVA. Overall, the study demonstrated how differences in polymer hygroscopicity and hydrogen bonding with sugars influence the stability of colyophilized amorphous dispersions. These insights into excipient solid-state stability are relevant to the development of stabilized biopharmaceutical solid-state formulations.