Insights into Factors Affecting Ethylene-Vinyl Acetate Copolymer Crystallinity in Islatravir Implant.

Islatravir, a highly potent nucleoside reverse transcriptase translocation inhibitor (NRTTI) for the treatment of HIV, has great potential to be formulated as ethylene-vinyl acetate (EVA) copolymer-based implants via hot melt extrusion. The crystallinity of EVA determines its physical and rheological properties and may impact the drug-eluting implant performance. Herein, we describe the systematic analysis of factors affecting the EVA crystallinity in islatravir implants. Differential scanning calorimetry (DSC) on EVA and solid-state NMR revealed drug loading promoted EVA crystallization, whereas BaSO4 loading had negligible impact on EVA crystallinity. The sterilization through γ-irradiation appeared to significantly impact the EVA crystallinity and surface characteristics of the implants. Furthermore, DSC analysis of thin implant slices prepared with an ultramicrotome indicated that the surface layer of the implant was more crystalline than the core. These findings provide critical insights into factors affecting the crystallinity, mechanical properties, and physicochemical properties of the EVA polymer matrix of extruded islatravir implants.

Leveraging ToF-SIMS imaging to investigate tenofovir disoproxil fumarate degradation at excipient interfaces in oral compressed tablets.

Time-of-flight secondary ion mass spectrometry (ToF-SIMS) imaging has been used to study the hydrolysis of tenofovir disoproxil fumarate (TDF) to tenofovir monosoproxil (TM) within an oral compressed tablet. The ToF-SIMS images displayed a heterogenous distribution of the matrix components. Evaluation of the TM distribution revealed that it was primarily co-localized with areas of higher excipient concentration pointing toward excipient driven degradation. To support these observations, a compatibility study of TDF with each tablet component was performed via liquid chromatography. The ToF-SIMS imaging and compatibility study indicated that the excipient, Avicel® PH-102, was the primary driver of TM formation in the tablet. The hydrolysis degradation mechanism within the tablet is further rationalized through discussion of chemical and physical properties of the matrix components. The sum of this work demonstrates a new analytical workflow for probing and understanding matrix driven degradation in oral compressed tablets utilizing ToF-SIMS imaging.

Impact of Processing Methods on the Physico-chemical Properties of Posaconazole Amorphous Solid Dispersions.

BACKGROUND & PURPOSE: Different methods have been exploited to generate amorphous solid dispersions (ASDs) of poorly water-soluble drugs. However, the impact of processing methods on drug stability and dissolution hasn't been studied extensively. The purpose of the current study is to investigate the impact of the two common ASD processing methods, hot-melt extrusion (HME) and spray drying, on the chemical/physical stability and supersaturation of Posaconazole (Posa) based ASDs. METHODS & RESULTS: ASDs with 25% drug loading in hydroxypropylmethylcellulose acetate succinate were prepared using HME, and two types of spray dryers, a Procept Sprayer (ASD-Procept) and a Nano Sprayer (ASD-Nano). The relative physical stability of these ASDs upon exposure to heat and crystalline API seeding followed the order: ASD-Nano > ASD-Procept ≈HME. ASD-Procept and ASD-Nano showed similar chemical stability, slightly less stable than HME under 40°C/75%RH. All three ASDs demonstrated similar supersaturation induction times, and de-supersaturation kinetics with or without crystalline seeds. CONCLUSIONS: Posa ASDs prepared via spray drying were chemically less stable compared with HME, which can be attributed to their smaller particle size and hollow structure allowing oxygen penetration. For ASD-Procept and HME, the detailed phase changes involving recrystallization of amorphous Posa and a solid-solid phase transition from Posa Form I to Form Ia during the seed-induced studies were proposed. Similar dissolution and supersaturation-precipitation kinetics of three Posa ASDs indicated that any residual nanocrystals in the bulk ASDs were not enough to induce crystallization to differentiate ASDs made by three processing methods.

Evaluating Spray Drying and Co-Precipitation as Manufacturing Processes for Amorphous Solid Dispersions of a Low Tg API.

Amorphous solid dispersions feature prominently in the approach to mitigate low bioavailability of poorly water-soluble small molecules, particularly in the early development space focusing on toxicity evaluations and clinical studies in normal healthy volunteers, where high exposures are needed to establish safety margins. Spray drying has been the go-to processing route for a number of reasons, including ubiquitous availability of equipment, the ability to accommodate small scale deliveries, and established processes for delivering single phase amorphous material. Active pharmaceutical ingredients (APIs) with low glass transition temperatures (Tg) can pose challenges to this approach. This study addresses multiple routes towards overcoming issues encountered with a low Tg (∼ 12 °C) API during manufacture of a spray dry intermediate (SDI). Even once formulated as an amorphous solid dispersion (ASD) with HPMCAS-LG, the Tg of the ASD was sufficiently low to require the use of non-ideal solvents, posing safety concerns and ultimately resulting in low yields with frequent process interruptions to resolve product build-up. To resolve challenges with spray drying the HPMCAS-L SDI, higher Tg polymers were assessed during spray drying, and an alternative antisolvent precipitation-based process was evaluated to generate co-precipitated amorphous dispersions (cPAD) with either HPMCAS-L or the additional higher Tg polymers. Both approaches were found to be viable alternatives to achieve single phase ASDs while demonstrating comparable in vitro and in vivo bioperformance compared to the SDI. The results of this effort offer valuable considerations for future early-stage activities for ASDs with low Tg APIs.

Detrimental Effect of the Film Coat Chemistry and Thickness on the Physical Stability of Amorphous Solid Dispersions in Tablet Formulations.

Amorphous solid dispersions (ASDs) have been widely utilized to enhance the bioavailability of pharmaceutical drugs with poor aqueous solubility. The role of various excipients on the amorphous drug to crystalline form conversion in ASDs has been widely documented. However, there has been no published study to investigate the role of film coating material on the physical stability of an ASD based tablet formulation, to the best of our knowledge. Here we show that the film coating can potentially have a detrimental impact on the physical stability of spray dried intermediates (SDI) in tablet formulations. The impact of the film coating on the physical stability of SDI was found to be related to the film coat material composition, and an increase in the film coating thickness led to a reduction in the physical stability of SDI in tablets. Oral compressed tablets in which the film coat material was "mixed-in" with the formulation blend showed a similar or worse physical stability than film coated tablets, further underscoring the film coat material impact on physical stability, independent of the film coating process. This study demonstrates a need for careful consideration of the film coat material selection for ASD based pharmaceutical product development.

Impact of Hydroxypropyl Methylcellulose Acetate Succinate Critical Aggregation Concentration on Celecoxib Supersaturation.

Polymers play an important role in amorphous solid dispersions (ASDs), enhancing stability in the solid state and maintaining supersaturation in aqueous solutions of intrinsically low-water-soluble drug candidates. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is widely used in ASDs due to its hydrophobic/hydrophilic balance and ionizability of the substituent functionalities. While colloid formation of HPMCAS in solution due to this hydrophobic/hydrophilic balance has been studied, the impact of the polymer conformation (random coil vs aggregated) on drug supersaturation of ASDs is not well understood. To our knowledge, this is the first report where the critical aggregation concentration for three grades of HPMCAS (HF/MF/LF) has been determined via fluorescence spectroscopy using the environment-sensitive probe pyrene. The specific impact of polymer conformation (random coil vs aggregate) on the model drug celecoxib (CLX) has been elucidated with fluorescence quenching and nuclear magnetic resonance (NMR) spectroscopy. A negative deviation of the Stern-Volmer plot indicated that aggregated HPMCAS effectively blocked the quencher's access to CLX. This is further supported by NMR observations, where NMR spectra indicate a larger change of chemical shift of the -NH group of CLX when HPMCAS is above its aggregated concentration, suggesting strong H-bonding interactions between aggregated HPMCAS and CLX. Finally, the supersaturation-precipitation study shows that all three grades of HPMCAS in the aggregated state significantly enhanced CLX supersaturation compared to the nonaggregated state, indicating that polymer aggregation plays a critical role in maintaining drug supersaturation.

Automated PET-RAFT Polymerization Towards Pharmaceutical Amorphous Solid Dispersion Development.

In pharmaceutical oral drug delivery development, about 90% of drugs in the pipeline have poor aqueous solubility leading to severe challenges with oral bioavailability and translation to effective and safe drug products. Amorphous solid dispersions (ASDs) have been utilized to enhance the oral bioavailability of poorly soluble active pharmaceutical ingredients (APIs). However, a limited selection of regulatory-approved polymer excipients exists for the development and further understanding of tailor-made ASDs. Thus, a significant need exists to better understand how polymers can be designed to interact with specific API moieties. Here, we demonstrate how an automated combinatorial library approach can be applied to the synthesis and screening of polymer excipients for the model drug probucol. We synthesized a library of 25 random heteropolymers containing one hydrophilic monomer (2-hydroxypropyl acrylate (HPA)) and four hydrophobic monomers at varied incorporation. The performance of ASDs made by a rapid film casting method was evaluated by dissolution using ultra-performance liquid chromatography (UPLC) sampling at various time points. This combinatorial library and rapid screening strategy enabled us to identify a relationship between polymer hydrophobicity, monomer hydrophobic side group geometry, and API dissolution performance. Remarkably, the most effective synthesized polymers displayed slower drug release kinetics compared to industry standard polymer excipients, showing the ability to modulate the drug release profile. Future coupling of high throughput polymer synthesis, high throughput screening (HTS), and quantitative modeling would enable specification of designer polymer excipients for specific API functionalities.

Engineered Hydrophobin as a Crystallization Inhibitor for Flufenamic Acid.

Hydrophobins are multifunctional, highly surface-active proteins produced in filamentous fungi. Due to their surface-active properties, resistance to degradation, and potential immunological inertness, hydrophobins have been used in many applications such as protein purification, increasing implant biocompatibility, increasing water solubility of insoluble drugs, and foam stabilizers for food products. To further explore surface-active and self-assembly properties of hydrophobins, we evaluated an engineered, recombinant hydrophobin (class II type 1, HFB1) as a potential crystallization inhibitor for maintaining drug supersaturation for an amorphous drug delivery system. A supersaturation-precipitation method was employed utilizing an ultraviolet (UV) fiber optic system for tracking precipitation kinetics of a model drug, flufenamic acid (FA), that was selected due to its low aqueous solubility in its crystalline form. The effectiveness of HFB1 as a crystallization inhibitor was compared with commonly used pharmaceutical grade polymeric crystallization inhibitors. The following polymers were selected to compare with HFB1: methocel (A4C grade), methocel (K15M grade), Kollidon vinylpyrrolidone-vinyl acetate (VA64), and hydroxypropyl methylcellulose acetate succinate (HPMCAS) (MF grade). The supersaturation-precipitation experiments concluded that HFB1 outperformed all polymers tested in this study and can potentially be used as a crystallization inhibitor at significantly lower concentrations in amorphous drug delivery systems. Dynamic light scattering (DLS) and circular dichroism (CD) results suggest a crystallization inhibition mechanism in which HFB1 functions differently depending on whether flufenamic acid is molecularly dispersed but supersaturated relative to its crystalline solubility or it has exceeded its amorphous solubility limit and exists as a phase-separated drug-rich colloid.

Quantifying Molecular Mixing and Heterogeneity in Pharmaceutical Dispersions at Sub-100 nm Resolution by Spin Diffusion NMR.

Molecular miscibility and homogeneity of amorphous solid dispersions (ASDs) are critical attributes that impact physicochemical stability, bioavailability, and processability. Observation of a single glass transition is utilized as a criterion for good mixing of drug substance and polymeric components but can be misleading and cannot quantitatively analyze the domain size at high resolution. While imaging techniques, on the other hand, can characterize phase separation on the particle surface at the nanometer scale, they often require customized sample preparation and handling. Moreover, a mixed system is not necessarily homogeneous. Compared to the numerous studies that have evaluated the mixing of drug substance and polymer in ASDs, inhomogeneity in the phase compositions has remained significantly underexplored. To overcome the analytical challenge, we have developed a 1H spin diffusion NMR technique to quantify molecular mixing of bulk ASDs at sub-100 nm resolution. It combines relaxation filtering (T2H and T1ρ) that leaves the active pharmaceutical ingredient (API) as the main source of 1H magnetization at the start of spin diffusion to the polymer matrix. A spray-dried nifedipine-poly(vinylpyrrolidone) (Nif-PVP) ASD at a 5 wt % drug loading was a homogeneous reference system that exhibited equilibration of magnetization transfer from API to polymer within a short spin diffusion time of ∼3 ms. While fast initial magnetization transfer proving mixing on the 1 nm scale was also observed in Nif-PVP ASDs prepared by hot-melt extrusion (HME) at 186 °C at a 40 wt % drug loading, incomplete equilibration of peak intensities documented inhomogeneity on the ≥30 nm scale. The nonuniformity was confirmed by the partial inversion of the Nif magnetization in the filter that resulted in an even more pronounced deviation from equilibration and by 1H-13C heteronuclear correlation (HETCOR) NMR. It is consistent with the observed differential 1H spin-lattice relaxation of Nif and PVP as well as a domain structure on the 20 nm scale observed in atomic force microscopy (AFM) images. The incomplete equilibration and differential relaxation were consistently reproduced in a model of two mixed phases of different compositions, e.g., 40 wt % of the ASD with a 15 wt % drug loading and the remaining 60 wt % with a 56 wt % drug loading. Hot-melt extrusion produced more inhomogeneous samples than spray drying for the samples examined in our study. To the best of our knowledge, this spin diffusion NMR method provides currently the highest-resolution quantification of inhomogeneous molecular mixing and phase composition in bulk samples of pharmaceutical dispersions produced with equipment, procedures, and drug loadings that are relevant to industrial drug development.

Evaluation of telepharmacy and the use of a gravimetric technology-assisted workflow system for remote sterile product pharmacist checks.

PURPOSE: To evaluate the impact of remote sterile product pharmacist checks when used with a gravimetric-based technology-assisted workflow (TAWF) system on product checking accuracy, pharmacist review time, workload sharing, cost savings, and staff perceptions. METHODS: A double-arm, prospective study was conducted at 4 pharmacy locations for a 90-day period. Each compounded sterile product (CSP) checked by a remote pharmacist was also checked by a local pharmacist at the site of CSP preparation. An anonymous, online survey was emailed to staff before and after implementation to evaluate perceptions of the accuracy, timeliness, safety, potential impact, and value of the remote process. RESULTS: There was no statistically significant difference in the numbers of errors detected through the remote process and through the current, nonremote process (P = 0.177). The median pharmacist review time in the local process was significantly lower (P < 0.001). Remote pharmacists in the study workflow verified 30.4% of the total number of CSPs verified in the 90-day period. Annualized cost savings were calculated to be $23,770.08. Percent agreement increased from the preimplementation to the postimplementation period for survey questions about the safety of the remote process, opportunity for workload sharing, and optimization of current workflow. Percent agreement decreased for questions about the accuracy, timeliness, and value of the remote process and its impact on job security. CONCLUSION: The study demonstrated that with use of a gravimetric-based TAWF system, there was no difference in the accuracy and safety of sterile product pharmacist checks performed remotely and those performed at the product preparation site. In addition, the remote process allows for opportunities for workload sharing and cost savings.

The peptide hormone glucagon forms amyloid fibrils with two coexisting ß-strand conformations.

Glucagon and insulin maintain blood glucose homeostasis and are used to treat hypoglycemia and hyperglycemia, respectively, in patients with diabetes. Whereas insulin is stable for weeks in its solution formulation, glucagon fibrillizes rapidly at the acidic pH required for solubility and is therefore formulated as a lyophilized powder that is reconstituted in an acidic solution immediately before use. Here we use solid-state NMR to determine the atomic-resolution structure of fibrils of synthetic human glucagon grown at pharmaceutically relevant low pH. Unexpectedly, two sets of chemical shifts are observed, indicating the coexistence of two ß-strand conformations. The two conformations have distinct water accessibilities and intermolecular contacts, indicating that they alternate and hydrogen bond in an antiparallel fashion along the fibril axis. Two antiparallel ß-sheets assemble with symmetric homodimer cross sections. This amyloid structure is stabilized by numerous aromatic, cation-π, polar and hydrophobic interactions, suggesting mutagenesis approaches to inhibit fibrillization could improve this important drug.

Detecting and Quantifying Microscale Chemical Reactions in Pharmaceutical Tablets by Stimulated Raman Scattering Microscopy.

It has been estimated that approximately 50% of all marketed drug molecules are manufactured and administered in the form of salts, often with the goal of improving solubility, dissolution rate, and efficacy of the drug. However, salt disproportionation during processing or storage is a common adverse effect in these formulations. Due to the heterogeneous nature of solid drug formulations, it is essential to characterize the drug substances noninvasively at micrometer resolution to understand the molecular mechanism of salt disproportionation. However, there is a lack of such capability with current characterization methods. In this study, we demonstrate that stimulated Raman scattering (SRS) microscopy can be used to provide sensitive and quantitative chemical imaging of the salt disproportionation reaction of pioglitazone hydrochloride (PIO-HCl) at a very low drug loading (1% w/w). Our findings illuminate a water mediated pathway of drug disproportionation and highlight the importance of noninvasive chemical imaging in a mechanistic study of solid-state chemical reactions.

In Situ Stimulated Raman Scattering (SRS) Microscopy Study of the Dissolution of Sustained-Release Implant Formulation.

Localized drug delivery systems (DDSs) provide therapeutic levels of drug agent while mitigating side effects of systemic delivery. These systems offer controlled release over extended periods of time making them attractive therapies. Monitoring drug dissolution is vital for developing safe and effective means of drug delivery. Currently, dissolution characterization methods are limited to bulk analysis and cannot provide dissolution kinetics at high spatial resolution. However, dissolution rates of drug particles can be heterogeneous with influences from many factors. Insights into finer spatiotemporal dynamics of single particle dissolution could potentially improve pharmacokinetic modeling of dissolution for future drug development. In this work, we demonstrate high-resolution chemical mapping of entecavir, a hepatitis B antiviral drug, embedded in a slow release poly(d,l-lactic acid) formulation with stimulated Raman scattering (SRS) microscopy. By tracking the volume change of individual micron-sized drug particles within the polymer matrix, we establish an analytical protocol for quantitatively profiling dissolution of single crystalline particles in implant formulations in an in situ manner.

Insights into Nano- and Micron-Scale Phase Separation in Amorphous Solid Dispersions Using Fluorescence-Based Techniques in Combination with Solid State Nuclear Magnetic Resonance Spectroscopy.

PURPOSE: Miscibility between the drug and the polymer in an amorphous solid dispersion (ASD) is considered to be one of the most important factors impacting the solid state stability and dissolution performance of the active pharmaceutical ingredient (API). The research described herein utilizes emerging fluorescence-based methodologies to probe (im)miscibility of itraconazole (ITZ)-hydroxypropyl methylcellulose (HPMC) ASDs. METHODS: The ASDs were prepared by solvent evaporation with varying evaporation rates and were characterized by steady-state fluorescence spectroscopy, confocal imaging, differential scanning calorimetry (DSC), and solid state nuclear magnetic resonance (ssNMR) spectroscopy. RESULTS: The size of the phase separated domains for the ITZ-HPMC ASDs was affected by the solvent evaporation rate. Smaller domains (<10 nm) were observed in spray-dried ASDs, whereas larger domains (>30 nm) were found in ASDs prepared using slower evaporation rates. Confocal imaging provided visual confirmation of phase separation along with chemical specificity, achieved by selectively staining drug-rich and polymer-rich phases. ssNMR confirmed the results of fluorescence-based techniques and provided information on the size of phase separated domains. CONCLUSIONS: The fluorescence-based methodologies proved to be sensitive and rapid in detecting phase separation, even at the nanoscale, in the ITZ-HPMC ASDs. Fluorescence-based methods thus show promise for miscibility evaluation of spray-dried ASDs.

Assessing Mixing Quality of a Copovidone-TPGS Hot Melt Extrusion Process with Atomic Force Microscopy and Differential Scanning Calorimetry.

Atomic force microscopy (AFM) and modulated differential scanning calorimetry (mDSC) were used to evaluate the extent of mixing of a hot melt extrusion process for producing solid dispersions of copovidone and D-α-tocopherol polyethylene glycol 1000 succinate (TPGS 1000). In addition to composition, extrusion process parameters of screw speed and thermal quench rate were varied. The data indicated that for 10% TPGS and 300 rpm screw speed, the mixing was insufficient to yield a single-phase amorphous material. AFM images of the extrudate cross section for air-cooled material indicate round domains 200 to 700 nm in diameter without any observed alignment resulting from the extrusion whereas domains in extrudate subjected to chilled rolls were elliptical in shape with uniform orientation. Thermal analysis indicated that the domains were predominantly semi-crystalline TPGS. For 10% TPGS and 600 rpm screw speed, AFM and mDSC data were consistent with that of a single-phase amorphous material for both thermal quench rates examined. When the TPGS concentration was reduced to 5%, a single-phase amorphous material was achieved for all conditions even the slowest screw speed studied (150 rpm).

Using lean principles to improve outpatient adult infusion clinic chemotherapy preparation turnaround times.

PURPOSE: The workflow and chemotherapy preparation turnaround times at an adult infusion clinic were evaluated to identify opportunities to optimize workflow and efficiency. METHODS: A three-phase study using Lean Six Sigma methodology was conducted. In phase 1, chemotherapy turnaround times in the adult infusion clinic were examined one year after the interim goal of a 45-minute turnaround time was established. Phase 2 implemented various experiments including a five-day Kaizen event, using lean principles in an effort to decrease chemotherapy preparation turnaround times in a controlled setting. Phase 3 included the implementation of process-improvement strategies identified during the Kaizen event, coupled with a final refinement of operational processes. RESULTS: In phase 1, the mean turnaround time for all chemotherapy preparations decreased from 60 to 44 minutes, and a mean of 52 orders for adult outpatient chemotherapy infusions was received each day. After installing new processes, the mean turnaround time had improved to 37 minutes for each chemotherapy preparation in phase 2. In phase 3, the mean turnaround time decreased from 37 to 26 minutes. The overall mean turnaround time was reduced by 26 minutes, representing a 57% decrease in turnaround times in 19 months through the elimination of waste and the implementation of lean principles. This reduction was accomplished through increased efficiencies in the workplace, with no addition of human resources. CONCLUSION: Implementation of Lean Six Sigma principles improved workflow and efficiency at an adult infusion clinic and reduced the overall chemotherapy turnaround times from 60 to 26 minutes.

Probing the effect of drug loading and humidity on the mechanical properties of solid dispersions with nanoindentation: antiplasticization of a polymer by a drug molecule.

Amorphous solid dispersions of clotrimazole in the polymer Kollidon VA64 were prepared as films in concentrations from 0% to 100% in 10% by weight increments. Nanoindentation was performed on each film at 18% and 49% relative humidity to assess the effect of drug loading and humidity on the mechanical properties of the solid dispersions. Although the addition of clotrimazole to the polymer reduces the glass transition temperature of the system as measured by differential scanning calorimetry, the hardness, reduced elastic modulus, and storage modulus were found to increase to values greater than those of either pure component up to drug loadings of approximately 60% by weight. Further addition of clotrimazole to the system resulted in decreased hardness and moduli with increased drug load. Dynamic vapor sorption of the dispersions shows that the hygroscopicity of the system is reduced as clotrimazole is added to the polymer.

Peptide--silica hybrid networks: biomimetic control of network mechanical behavior.

Self-assembly represents a robust and powerful paradigm for the bottom-up construction of nanostructures. Templated condensation of silica precursors on self-assembled nanoscale peptide fibrils with various surface functionalities can be used to mimic biosilicification. This template-defined approach toward biomineralization was utilized for the controlled fabrication of 3D hybrid nanostructures. The peptides MAX1 and MAX8 used herein form networks consisting of interconnected, self-assembled beta-sheet fibrils. We report a study on the structure--property relationship of self-assembled peptide hydrogels where mineralization of individual fibrils through sol--gel chemistry was achieved. The nanostructure and consequent mechanical characteristics of these hybrid networks can be modulated by changing the stoichiometric parameters of the sol--gel process. The physical characterization of the hybrid networks via electron microscopy and small-angle scattering is detailed and correlated with changes in the network mechanical behavior. The resultant high fidelity templating process suggests that the peptide substrate can be used to template the coating of other functional inorganic materials.