Patrick J. Marsac

Phase Behavior of Poly(vinylpyrrolidone) Containing Amorphous Solid Dispersions in the Presence of Moisture

The objective of this study was to investigate the phase behavior of amorphous solid dispersions composed of a hydrophobic drug and a hydrophilic polymer following exposure to elevated relative humidity. Infrared (IR) spectroscopy, differential scanning calorimetry (DSC) and moisture sorption analysis were performed on five model systems (nifedipine-poly(vinylpyrrolidone) (PVP), indomethacin-PVP, ketoprofen-PVP, droperidol-PVP, and pimozide-PVP) immediately after production of the amorphous solid dispersions and following storage at room temperature and elevated relative humidity. Complete miscibility between the drug and the polymer immediately after solid dispersion formation was confirmed by the presence of specific drug-polymer interactions and a single glass transition (T(g)) event. Following storage at elevated relative humidity (75-94% RH), nifedipine-PVP, droperidol-PVP, and pimozide-PVP dispersions formed drug-rich and polymer-rich amorphous phases prior to crystallization of the drug, while indomethacin-PVP and ketoprofen-PVP dispersions did not. Drug crystallization in systems exhibiting amorphous-amorphous phase separation initiated earlier (<6 days at 94% RH) when compared to systems that remained miscible (>or=46 days at 94% RH). Evidence of moisture-induced amorphous-amorphous phase separation was observed following storage at as low as 54% RH for the pimozide-PVP system. It was concluded that, when an amorphous molecular level solid dispersion containing a hydrophobic drug and hydrophilic polymer is subjected to moisture, drug crystallization can occur via one of two routes: crystallization from the plasticized one-phase solid dispersion, or crystallization from a plasticized drug-rich amorphous phase in a two-phase solid dispersion. In the former case, the polymer is still present in the same phase as the drug, and can inhibit crystallization to a greater extent than the latter scenario, where the polymer concentration in the drug phase is reduced as a result of the amorphous-amorphous phase separation. The strength of drug-polymer interactions appears to be important in influencing the phase behavior.

Size Selectivity of Intestinal Mucus to Diffusing Particulates is Dependent on Surface Chemistry and Exposure to Lipids

Abstract Intestinal mucus provides a significant barrier to transport of orally delivered drug carriers, as well as other particulates (e.g. food, microbes). The relative significance of particle size, surface chemistry, and dosing medium to mucus barrier properties is not well characterized, but important in designing delivery systems targeted to the intestinal mucosa. In this study, multiple particle tracking (MPT) was used to study diffusion of 20–500 nm diameter carboxylate- and polyethylene glycol-(PEG-)functionalized polystyrene model carriers through intestinal mucus. The impact of exposure to mucus in buffer versus a partially digested triglyceride mixture was explored. Effective diffusivity of particles in intestinal mucus decreased with an increasing particle size less than and more than theoretically (Stokes–Einstein) expected in a homogenous medium when dosed in buffer and model-fed state intestinal contents, respectively. For example, effective diffusivity decreased 2.9- versus 20-fold with increase in the particle size from 100 to 500 nm when dosed to mucus in buffer versus lipid-containing medium. Functionalization with PEG dramatically decreased sensitivity to lipids in a dosing medium. The results indicate that reduction of particle size may increase particle transport through intestinal mucus barriers, but these effects are strongly dependent on intestinal contents and particle surface chemistry.

Analytical approaches to investigate salt disproportionation in tablet matrices by Raman spectroscopy and Raman mapping.

It has always been challenging to use spectroscopic methods to analyze salt disproportionation in a multi-component tablet matrix due to the spectral interference generated by the various excipients. Although combining Raman spectroscopy and chemometrics can be a powerful approach to study the extent of salt disproportionation, it was found in the present study that bulk measurements and chemometric modeling have obvious limitations when the targeted component is present at low levels in the tablet. Hence, a two-step Raman mapping approach was developed herein to investigate salt disproportionation in tablets with a low drug loading (5% w/w). The first step is to locate the area of interest where the drug particles reside throughout the tablet surface by using a statistically optimized sampling method termed deliberate sub-sampling. The second step, referred to herein as close-step mapping, utilize a step by step mapping of the targeted area to find more details of salt disproportionation in the tablet regions where the drug is concentrated. By using this two-step Raman mapping approach, we successfully detected the existence of minor species embedded in multi-component low drug loading tablet matrices, where bulk measurements from routine techniques usually lack of sensitivity. This approach will help formulation scientists detect and understand salt disproportionation and in situ drug-excipients compatibility issues in low dose solid dosage formulations.

Impact of polymer type on bioperformance and physical stability of hot melt extruded formulations of a poorly water soluble drug

Amorphous solid dispersion formulations have been widely used to enhance bioavailability of poorly soluble drugs. In these formulations, polymer is included to physically stabilize the amorphous drug by dispersing it in the polymeric carrier and thus forming a solid solution. The polymer can also maintain supersaturation and promote speciation during dissolution, thus enabling better absorption as compared to crystalline drug substance. In this paper, we report the use of hot melt extrusion (HME) to develop amorphous formulations of a poorly soluble compound (FaSSIF solubility=1μg/mL). The poor solubility of the compound and high dose (300mg) necessitated the use of amorphous formulation to achieve adequate bioperformance. The effect of using three different polymers (HPMCAS-HF, HPMCAS-LF and copovidone), on the dissolution, physical stability, and bioperformance of the formulations was demonstrated. In this particular case, HPMCAS-HF containing HME provided the highest bioavailability and also had better physical stability as compared to extrudates using HPMCAS-LF and copovidone. The data demonstrated that the polymer type can have significant impact on the formulation bioperformance and physical stability. Thus a thorough understanding of the polymer choice is imperative when designing an amorphous solid dispersion formulation, such that the formulation provides robust bioperformance and has adequate shelf life.

Hot-Melt Extrusion for Solid Dispersions: Composition and Design Considerations

Melt extrusion is a robust and efficient manufacturing platform that can be utilized for the production of amorphous dispersions. The development of these systems requires careful design of both formulation and process under a structured approach to ensure critical quality attributes are achieved and maintained. This chapter discusses specific aspects for selecting the manufacturing platform, developing and characterizing dispersions that are applicable to the compositional definition.

Crystalline solid dispersion-a strategy to slowdown salt disproportionation in solid state formulations during storage and wet granulation

Salt disproportionation (a conversion from the ionized to the neutral state) in solid formulations is a potential concern during manufacturing or storage of products containing a salt of the active pharmaceutical ingredient (API) due to the negative ramifications on product performance. However, it is challenging to find an effective approach to prevent or mitigate this undesirable reaction in formulations. Hence, the overall objective of this study is to explore novel formulation strategies to reduce the risk of salt disproportionation in pharmaceutical products. Crystals of pioglitazone hydrochloride salt were dispersed into polymeric matrices as a means of preventing the pharmaceutical salt from direct contact with problematic excipients. It was found that the level of salt disproportionation could be successfully reduced during storage or wet granulation by embedding a crystalline salt into a polymeric carrier. Furthermore, the impact of different polymers on the disproportionation process of a salt of a weakly basic API was investigated herein. Disproportionation of pioglitazone hydrochloride salt was found to be significantly affected by the physicochemical properties of different polymers including hygroscopicity and acidity of substituents. These findings provide an improved understanding of the role of polymeric carriers on the stability of a salt in solid formulations. Moreover, we also found that introducing acidifiers into granulation fluid can bring additional benefits to retard the disproportionation of pioglitazone HCl during the wet granulation process. These interesting discoveries offer new approaches to mitigate disproportionation of API salt during storage or processing, which allow pharmaceutical scientists to develop appropriate formulations with improved drug stability.

HME for Solid Dispersions: Scale-Up and Late-Stage Development

The advantages provided by melt extrusion over other amorphous dispersion manufacturing technologies make it uniquely suited for commercial applications. The proven scalability of the technology combined with the modular nature provides unmatched versatility. Extrusion has been utilized for dispersion manufacturing of commercial products across a range of scales and integrating with in-line monitoring technologies, it fully enables the benefits of continuous manufacturing. Novel applications, such as devolatilization and development using quality by design, allow for the technology to support both drug substance and drug product manufacturing.

Insights into Water-Induced Phase Separation in Itraconazole–Hydroxypropylmethyl Cellulose Spin Coated and Spray Dried Dispersions

For amorphous solid dispersions, understanding the phase behavior of a given drug-polymer blend and factors that influence miscibility is crucial to designing an optimally performing formulation. However, it can be challenging to fully map the phase behavior of some systems, especially those produced using a cosolvent system. In this study, a comprehensive investigation of phase separation in itraconazole-hydroxypropylmethylcellulose (ITZ-HPMC) blends fabricated using solvent evaporation processes, including spin coating and spray drying, has been carried out. Phase separation was found to be driven by the presence of water, either acquired from the environment or from the solvent system. ITZ nanospecies were observed during the solvent evaporation process prior to solidification. The use of high resolution imaging techniques such as transmission electron microscopy including bright field and high angle annular dark field imaging, enabled detailed characterization of the microstructure of phase separated systems. Spectroscopic investigations suggested that drug domains contain supramolecular drug aggregates in which the nematic assembly of ITZ molecules results in the coupling of the optical transitions of ITZ monomers. Importantly, a similar pattern of behavior between drug-polymer phase in spin coated and spray dried dispersions was observed. The presence of as little as 1% water in the solvent was found to induce phase separation in the spray dried particles, which was detected using the unique photophysical properties of ITZ and fluorescence spectroscopy. The study highlights the complexity of drug-polymer phase behavior and the influence of solvent properties.

Second harmonic generation microscopy as a tool for the early detection of crystallization in spray dried dispersions

HIGHLIGHTSSecond harmonic generation (SHG) microscopy was applied for sensitive detection of crystallinity in spray dried particles.SHG detected crystallinity at an earlier time point than X‐ray powder diffraction for two spray dried sytems.The SHG technique presented herein can be potentially used to rapidly evaluate the stability of different spray dried formulations to crystallization. ABSTRACT Various techniques have been used to detect crystallization in amorphous solid dispersions (ASD). However, most of these techniques do not enable the detection of very low levels of crystallinity (<1%). The aim of the current study was to compare the sensitivity of second harmonic generation (SHG) microscopy with powder X‐ray diffraction (XRPD) in detecting the presence of crystals in low drug loading amorphous solid dispersions. Amorphous solid dispersions of the poorly water soluble compounds, flutamide (FTM, 15 wt.% drug loading) and ezetimibe (EZT, 30 wt.% drug loading) with hydroxypropyl methylcellulose acetate succinate (HPMCAS) were prepared by spray drying. To induce crystallization, samples were subsequently stored at 75% or 82% relative humidity (RH) and 40 °C. Crystallization was monitored by XRPD and by SHG microscopy. Solid state nuclear magnetic resonance spectroscopy (ssNMR) was used to further investigate crystallinity in selected samples. For flutamide, crystals were detected by SHG microscopy after 8 days of storage at 40 °C/82% RH, whereas no evidence of crystallinity could be observed by XRPD until 26 days. Correspondingly, for FTM samples stored at 40 °C/75% RH, crystals were detected after 11 days by SHG microscopy and after 53 days by XRPD. The evolution of crystals, that is an increase in the number and size of crystalline regions, with time could be readily monitored from the SHG images, and revealed the formation of needle‐shaped crystals. Further investigation with scanning electron microscopy indicated an unexpected mechanism of crystallization, whereby flutamide crystals grew as needle‐shaped projections from the surface of the spray dried particles. Similarly, EZT crystals could be detected at earlier time points (15 days) with SHG microscopy relative to with XRPD (60 days). Thus, SHG microscopy was found to be a highly sensitive method for detecting and monitoring the evolution of crystals formed from spray dried particles, providing much earlier detection of crystallinity than XRPD under comparable run times.

Performance and Characterization of Amorphous Solid Dispersions: An Overview

In recent years the use of amorphous active pharmaceutical ingredients (API), adequately stabilized in a solid oral formulation, has attracted significant attention due to poor solubility of the crystalline forms of drug substances which often leads to inadequate bioavailability. These amorphous formulations, typically known as solid dispersions, exhibit higher solubility and dissolution rates than formulations prepared using the crystalline form of the API and hence can achieve higher bioavailability. However, since the amorphous form is inherently thermodynamically unstable as compared to the crystalline form, development of amorphous formulations also present unique challenges such as risk of crystallization of the API in the dosage form or during dissolution. In this chapter, we provide an overview of the oral drug absorption process, the formulation and physiological factors impacting drug absorption and the use of dimensionless numbers and absorption modeling in formulation selection. We provide an in-depth description of the concepts of supersaturation, crystallization, and speciation during dissolution, and their effect on product performance. Finally, solid-state failure modes such as crystallization and amorphous–amorphous phase separation in the dosage form are described along with techniques used to measure solid-state stability.