Amorphous-amorphous Phase Separation Research Articles

COSMOPharm: Drug-Polymer Compatibility of Pharmaceutical Amorphous Solid Dispersions from COSMO-SAC.

The quantum mechanics-aided COSMO-SAC activity coefficient model is applied and systematically examined for predicting the thermodynamic compatibility of drugs and polymers. The drug-polymer compatibility is a key aspect in the rational selection of optimal polymeric carriers for pharmaceutical amorphous solid dispersions (ASD) that enhance drug bioavailability. The drug-polymer compatibility is evaluated in terms of both solubility and miscibility, calculated using standard thermodynamic equilibrium relations based on the activity coefficients predicted by COSMO-SAC. As inherent to COSMO-SAC, our approach relies only on quantum-mechanically derived σ-profiles of the considered molecular species and involves no parameter fitting to experimental data. All σ-profiles used were determined in this work, with those of the polymers being derived from their shorter oligomers by replicating the properties of their central monomer unit(s). Quantitatively, COSMO-SAC achieved an overall average absolute deviation of 13% in weight fraction drug solubility predictions compared to experimental data. Qualitatively, COSMO-SAC correctly categorized different polymer types in terms of their compatibility with drugs and provided meaningful estimations of the amorphous-amorphous phase separation. Furthermore, we analyzed the sensitivity of the COSMO-SAC results for ASD to different model configurations and σ-profiles of polymers. In general, while the free volume and dispersion terms exerted a limited effect on predictions, the structures of oligomers used to produce σ-profiles of polymers appeared to be more important, especially in the case of strongly interacting polymers. Explanations for these observations are provided. COSMO-SAC proved to be an efficient method for compatibility prediction and polymer screening in ASD, particularly in terms of its performance-cost ratio, as it relies only on first-principles calculations for the considered molecular species. The open-source nature of both COSMO-SAC and the Python-based tool COSMOPharm, developed in this work for predicting the API-polymer thermodynamic compatibility, invites interested readers to explore and utilize this method for further research or assistance in the design of pharmaceutical formulations.

Characterizing Phase Separation of Amorphous Solid Dispersions Containing Imidacloprid.

Amorphous-Amorphous phase separation (AAPS) is an important phenomenon that can impede the performance of amorphous solid dispersions (ASDs). The purpose of this study was to develop a sensitive approach relying on dielectric spectroscopy (DS) to characterize AAPS in ASDs. This includes detecting AAPS, determining the size of the active ingredient (AI) discrete domains in the phase-separated systems, and accessing the molecular mobility in each phase. Using a model system consisting of the insecticide imidacloprid (IMI) and the polymer polystyrene (PS), the dielectric results were further confirmed by confocal fluorescence microscopy (CFM). The detection of AAPS by DS was accomplished by identifying the decoupled structural (α-)dynamics of the AI and the polymer phase. The α-relaxation times corresponding to each phase correlated reasonably well with those of the pure components, implying nearly complete macroscopic phase separation. Congruent with the DS results, the occurrence of the AAPS was detected by means of CFM, making use of the autofluorescent property of IMI. Oscillatory shear rheology and differential scanning calorimetry (DSC) detected the glass transition of the polymer phase but not that of the AI phase. Furthermore, the otherwise undesired effects of interfacial and electrode polarization, which can appear in DS, were exploited to determine the effective domain size of the discrete AI phase in this work. Here, stereological analysis of CFM images probing the mean diameter of the phase-separated IMI domains directly stayed in reasonably good agreement with the DS-based estimates. The size of phase-separated microclusters showed little variation with AI loading, implying that the ASDs have presumably undergone AAPS upon manufacturing. DSC provided further support to the immiscibility of IMI and PS, as no discernible melting point depression of the corresponding physical mixtures was detected. Moreover, no signatures of strong attractive AI-polymer interactions could be detected by mid-infrared spectroscopy within this ASD system. Finally, dielectric cold crystallization experiments of the pure AI and the 60 wt % dispersion revealed comparable crystallization onset times, hinting at a poor inhibition of the AI crystallization within the ASD. These observations are in harmony with the occurrence of AAPS. In conclusion, our multifaceted experimental approach opens new venues for rationalizing the mechanisms and kinetics of phase separation in amorphous solid dispersions.

Release Mechanisms of Amorphous Solid Dispersions: Role of Drug-Polymer Phase Separation and Morphology

Formulating poorly soluble molecules as amorphous solid dispersions (ASDs) is an effective strategy to improve drug release. However, drug release rate and extent tend to rapidly diminish with increasing drug loading (DL). The poor release at high DLs has been postulated to be linked to the process of amorphous-amorphous phase separation (AAPS), although the exact connection between phase separation and release properties remains somewhat unclear. Herein, release profiles of ASDs formulated with ritonavir (RTV) and polyvinylpyrrolidone/vinyl acetate (PVPVA) at different DLs were determined using surface normalized dissolution. Surface morphologies of partially dissolved ASD compacts were evaluated with confocal fluorescence microscopy, using Nile red and Alexa Fluor 488 as fluorescence markers to track the hydrophobic and hydrophilic phases respectively. ASD phase behavior during hydration and release of components were also visualized in real time using a newly developed in situ confocal fluorescence microscopy method. RTV-PVPVA ASDs showed complete and rapid drug release below 30% DL, partial drug release at 30% DL and no drug release above 30% DL. It was observed that formation of discrete drug-rich droplets at lower DLs led to rapid and congruent release of both drug and polymer, whereas formation of continuous drug-rich phase at the ASD matrix-solution interface was the cause of poor release above certain DLs. Thus, the domain size and interconnectivity of phase separated drug-rich domains appear to be critical factors impacting drug release from RTV-PVPVPA ASDs.

Compatibility of selected active pharmaceutical ingredients with poly(D, L-lactide-co-glycolide): Computational and experimental study

Biodegradable polyesters have emerged as a promising class of polymers for the development of efficient drug delivery systems for various treatments (including cancer treatment) due to their biocompatibility, low toxicity, and controlled drug release. This study presents a computational and experimental evaluation of the compatibility of selected model active pharmaceutical ingredients (APIs) with poly(D, L-lactide-co-glycolide) (PLGA), which is a key parameter to designing drug delivery systems based on amorphous solid dispersions (ASDs) and polymeric micro- or nanoparticles. PLGA with different molar ratios of the monomer units, i.e., lactide to glycolide ratio of 50:50 (PLGA50) or 75:25 (PLGA75), were investigated as polymeric carriers for the following model APIs: ibuprofen (IBU), paracetamol (PARA), naproxen (NAP), and indomethacin (IND). The phase diagrams obtained by a combination of calorimetric measurements and modeling using the perturbed-chain statistical associating fluid theory (PC-SAFT) equation of state (EOS) demonstrated low solubility of the model APIs in the studied copolymers at storage temperature (25 °C). The amorphous-amorphous phase separation was predicted by the PC-SAFT EOS for all API–PLGA systems and experimentally detected for the IBU–PLGA50, IBU–PLGA75, and NAP–PLGA75 systems. To investigate the physical stability of the API–PLGA systems and their link to the constructed phase diagrams, API–PLGA75 formulations were prepared using a melting process, and their solid-state properties were monitored over time. Of the analyzed API–PLGA75 formulations, only IND–PLGA75 remained in the amorphous state after 20 weeks of storage under dry conditions at 25 °C, while the other formulations recrystallized rapidly after preparation (IBU–PLGA75 and NAP–PLGA75) or after a limited storage period (PARA–PLGA75), reflecting poor compatibility of the investigated APIs with the PLGA copolymers and limited kinetic stabilization, as predicted from the constructed phase diagrams. Another important output of this work is the evaluation of the pure predictions of phase diagrams using the PC-SAFT EOS and its performance in ranking API–polymer compatibility.

Detecting different amorphous – Amorphous phase separation patterns in co-amorphous mixtures with high resolution imaging FTIR spectroscopy

Many active pharmaceutical ingredients (API) in development suffer from low aqueous solubilities. Instead of the crystal form, the amorphous state can be used to improve the API’s apparent solubility. However, the amorphous state has a higher Gibb’s free energy and is inherently unstable and tends to transform back to the more stable crystal form. In co-amorphous mixtures, phase separation needs to occur before there can be crystallization. The aim of this study was to devise a method to study amorphous-amorphous phase separation with high resolution imaging Fourier transform infrared (FTIR) spectroscopy with seven 1:1 M ratio API-API binary mixtures being examined. The binary mixtures were amorphized by melt-quenching and stored above their glass transition temperature (Tg) to monitor their phase separation. Thermodynamic properties (crystallization tendency, melting point (Tm) and Tg) of these mixtures were measured with differential scanning calorimetry (DSC) to verify the amorphization method and to assess the optimal storage temperature. The phase separation was examined with FTIR imaging in the transmission mode. Furthermore, measurements with two pure APIs were performed to ensure that the alterations occurring in the spectra were caused by phase separation not storage stress. In addition, the reproducibility of the imaging FTIR spectrometer was verified. The spectra were analyzed with principal component analysis (PCA) and a characteristic peak comparison method. Scatter-plots were produced from the amount of phase separated pixels in the measurement area as a way of visualizing the progress of phase separation. The results indicated that imaging with FTIR spectroscopy can produce reproducible results and the progress of phase separation can be detected as either a sigmoidal or as a start-to-finish linear pattern depending on the substances.

Phase separation in surfactant-containing amorphous solid dispersions: Orthogonal analytical methods to probe the effects of surfactants on morphology and phase composition

Amorphous–amorphous phase separation (AAPS) is an important phase transition process for amorphous solid dispersion (ASD) performance both in terms of drug release as well as physical and chemical stability during storage. Addition of surfactants to ASD systems can impact both of these processes. One possible mechanism through which surfactants affect ASD performance is via their impact on AAPS. Unfortunately, despite their increasing usage in ASD formulations, the effect of surfactant on AAPS is still poorly understood, and there are limited analytical techniques that provide microstructural and composition information about phase separated ASDs. In this study, the impact of four surfactants (sodium dodecyl sulfate, Tween 80, Span 20 and Span 85) on water-induced phase separation in ASDs formulated with ritonavir and polyvinylpyrrolidone/vinyl acetate (PVPVA) was investigated using a variety of orthogonal analytical methods. Transparent films of ASDs with different compositions were prepared by spin coating. Fluorescence confocal microscopy in combination with an in situ humidity chamber was used to monitor the kinetics and morphology of phase separation following exposure to high relative humidity. Optical photothermal IR analysis of phase separated films enabled characterization of domain composition and surfactant distribution. Liquid-liquid phase separation concentration, zeta potential and solution nuclear magnetic resonance spectroscopy measurements enabled interpretation of interaction with and partition of surfactants into the drug-rich phase. It was found that phase separation kinetics and morphology were notably changed by the surfactants. Further, the surfactants showed different affinities for the drug-rich versus the aqueous/polymer-rich phases. The employed analytical techniques were found to be complementary in providing insight into surfactant location in phase separated systems. This study highlights the complexity of phase separation, especially in the presence of surfactants, and provides a foundation to understand the impact of AAPS on ASD performance.

Influence of Particle Size and Drug Load on Amorphous Solid Dispersions Containing pH-Dependent Soluble Polymers and the Weak Base Ketoconazole

Among the great number of poorly soluble drugs in pharmaceutical development, most of them are weak bases. Typically, they readily dissolve in an acidic environment but are prone to precipitation at elevated pH. This was aimed to be counteracted by the preparation of amorphous solid dispersions (ASDs) using the pH-dependent soluble polymers methacrylic acid ethylacrylate copolymer (Eudragit L100–55) and hydroxypropylmethylcellulose acetate succinate (HPMCAS) via hot-melt extrusion. The hot-melt extruded ASDs were of amorphous nature and single phased with the presence of specific interactions between drug and polymer as revealed by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier-transform infrared spectroscopy (FT-IR). The ASDs were milled and classified into six particle size fractions. We investigated the influence of particle size, drug load, and polymer type on the dissolution performance. The best dissolution performance was achieved for the ASD made from Eudragit L100–55 at a drug load of 10%, whereby the dissolution rate was inversely proportional to the particle size. Within a pH-shift dissolution experiment (from pH 1 to pH 6.8), amorphous-amorphous phase separation occurred as a result of exposure to acidic medium which caused markedly reduced dissolution rates at subsequent higher pH values. Phase separation could be prevented by using enteric capsules (Vcaps Enteric®), which provided optimal dissolution profiles for the Eudragit L100–55 ASD at a drug load of 10%.

Raman imaging of amorphous-amorphous phase separation in small molecule co-amorphous systems

Many new active pharmaceutical ingredients (API) undergoing development have low permeabilities or low aqueous solubilities. However, the amorphous state is usually more soluble than its crystalline counterpart. The amorphous state has a higher Gibb’s free energy, which can improve the apparent solubility but decrease the stability since the amorphous state tends to transform to the more stable crystalline form. Before recrystallization, a co-amorphous binary mixture’s ingredients have to undergo a phase separation. The aim of this study was to obtain a better understanding of the amorphous-amorphous phase separation in co-amorphous binary mixtures and test the suitability of imaging Raman spectroscopy for detecting this phenomenon. To study the phase separation, we prepared three different 50:50 mass ratio binary mixtures of APIs: paracetamol-terfenadine, (PAR-TRF), paracetamol-indomethacin (PAR-IMC) and terfenadine-indomethacin (TRF-IMC). The binary mixtures were amorphized with melt-quenching and stored above their glass transition temperature (Tg) to monitor their phase separation. Thermal degradation was determined with a high performance liquid chromatography (HPLC) method to ensure that melt-quenching did not cause any thermal degradation of the molecules. Thermodynamic attributes (crystallization tendency, melting point (Tm) and Tg) were measured with differential scanning calorimetry (DSC) to ensure that the co-amorphous systems transformed to the amorphous state and remained amorphous after cooling and reheating. Phase separation was studied from the surface and cross-section (CS) with Raman imaging to examine if it occurred more on the surface than in the bulk. The Raman spectra were analyzed with principal component analysis (PCA) and Contour plots were produced from the PCA-score values to visualize concentration differences in the mixtures. The results showed that API vs API concentrations increased as a function of time in both surface and CS images before crystallization. This suggests that Raman imaging is a suitable technique to detect the phase separation phenomena in small molecule co-amorphous binary mixtures.

Detection of amorphous-amorphous phase separation in small molecular co-amorphous mixtures with SEM-EDS

Amorphicity is one possible way to increase the solubility of poorly water soluble drugs. However, amorphous solids are thermodynamically unstable and tend to recrystallize with material-specific kinetics. Crystallization is not the prime phenomenon in the whole process, although it is the easiest to measure. The primary phenomenon prior to the crystallization of glass is phase separation, the detection of which is very rarely reported among small molecular compounds. In the present study, a scanning electron microscope with energy dispersive X-ray spectrometer (SEM-EDS) was used to detect very early stage amorphous-amorphous phase separation in co-amorphous drug mixtures. Miscibility was calculated for five studied mixtures based on the Flory-Huggins method and four immiscible pairs and one partial miscible pair were selected for the laboratory experiments. Co-amorphous samples (n = 3) were prepared by melt-quench method and stored at the elevated temperature to induce the separation of amorphous phases. Each sample was stored at the same relative percentage temperature between glass transition temperature Tg and melting temperature Tm. Immediately after the sample preparation, the full amorphousness was verified with polarizing light microscopy. Before SEM-EDS analysis, the samples were fractured into two pieces and measurements were done from cross-section (from the bulk sample). All five pairs phase separated during two days of storage at the elevated temperature. The study proved that SEM-EDS was able to detect a very small phase separated regions in the amorphous sample, as amorphous-amorphous phase separation was detected in four out of five pairs. However, the surface roughness could affect the analysis and give a false indication of phase separation. SEM-EDS also supported calculation results, since every studied pair showed phase separation during study, as was predicted on the grounds of Flory-Huggins miscibility calculation.

The influence of crushing amorphous solid dispersion dosage forms on the in-vitro dissolution kinetics.

Solid dosage forms of amorphous solid dispersions (ASDs) have rarely been assessed for their crushability, although it might possibly be a more frequent practice than thought to facilitate oral administration in several clinical conditions (e.g. dysphagia) when no oral liquids of the same drug are available. Nevertheless, there are concerns that contraindicate these formulations' modification by grinding. For example, amorphous-amorphous phase separation, induction of crystallization, decreasing particle sizes, etc. might occur during grinding without knowing the implications on bioavailability. Hence, in this study, Sporanox® (itraconazole), Intelence® (etravirine), Noxafil® (posaconazole) and Norvir® (ritonavir), were selected as "model" enabling formulations (based on ASD) to evaluate if this concern was justified. Their assessment in simple and biorelevant media by two-stage in-vitro drug-release testing was performed which resulted in strong suspicion that pulverization is contradicted for some of these formulations. Despite differences were observed, uncertainty remains on the clinical relevance of these data as by golden standard it should still be confirmed by bioequivalence trials.

Direct Visualization of Drug-Polymer Phase Separation in Ritonavir-Copovidone Amorphous Solid Dispersions Using in situ Synchrotron X-ray Fluorescence Imaging of Thin Films.

Amorphous solid dispersions (ASDs) are new formulations currently being used in pharmaceutical industry. The ASDs, in which amorphous drug and polymeric excipients are intimately mixed at the molecular level, exhibit dramatically enhanced solubility and dissolution characteristics relative to their crystalline drug counterparts. In the process of achieving an ever-increasing drug loading (DL), it is noticed, however, that the drug release profile deteriorates significantly beyond a certain DL. As an example, a ritonavir-copovidone ASD achieves continuous and full drug release when DL ≤ 25 wt %. The release drops at 30 wt % and when DL ≥ 35 wt % there is virtually no drug release, behaving like a pure amorphous drug. In this Communication, the phase miscibility of ASD thin films has been investigated by in situ synchrotron X-ray fluorescence (XRF) imaging to elucidate the mechanism for the unique change in the extent of drug release as a function of DL. It is found that the drug release profile correlates well with the amorphous-amorphous phase separation (AAPS) onset. At a lower drug loading (up to 20 wt %), it takes more than 12 h for AAPS to happen while in sharp contrast, it only needs less than 10 min for DL ≥ 32.5 wt %. During AAPS, amorphous drug accumulates on the surface of the film, which prevents further dissolution from the interior of the ASD. The current study provides a mechanistic understanding of the confounding drug release profile of ASDs as a function of DL and opens the door for studying drug-excipient (e.g., polymer, surfactant) interactions via XRF imaging in the future.

Microstructure Formation for Improved Dissolution Performance of Lopinavir Amorphous Solid Dispersions.

Amorphous solid dispersions (ASDs), where the drug is dispersed in a polymer, have become increasingly prevalent as a formulation strategy for the oral delivery of poorly soluble drugs due to their potential for substantial solubility enhancement. However, ASDs are susceptible to amorphous-amorphous phase separation, which may promote crystallization and/or alter the release performance. Nevertheless, the mechanisms by which phase separation and subtle microstructural changes affect ASD release remain poorly understood. Therefore, understanding the microstructure of ASDs and the subsequent implication for ASD performance are critical to design an optimally performing formulation. In this study, comprehensive investigations of microstructure evolution in lopinavir ASDs, prepared using a solvent-based process, were undertaken. Atomic force microscopy (AFM)-based nanoscale thermal analysis (nanoTA) enabled characterization of local composition at the submicron scale. The formation of heterogeneous domains was found to improve the in vitro release of lopinavir from lopinavir-hydroxypropylmethylcellulose (HPMC) ASDs for drug loadings above 33% w/w. The composition and amount of each phase formed, as well as the size and location of drug-rich phases, were found to be critical factors contributing to the altered release kinetics observed. This study highlights the complexity and importance of ASD microstructure and should contribute to a broader understanding of ASD release mechanisms.

Insights into the Dissolution Mechanism of Ritonavir-Copovidone Amorphous Solid Dispersions: Importance of Congruent Release for Enhanced Performance.

The aim of this study was to probe the dissolution mechanisms of amorphous solid dispersions (ASDs) of a poorly water-soluble drug formulated with a hydrophilic polymer. Ritonavir (RTV) and polyvinylpyrrolidone/vinyl acetate (PVPVA) were used as the model drug and polymer, respectively. ASDs with drug loadings (DLs) from 10 to 50 wt % were prepared by solvent evaporation. Surface-normalized dissolution experiments were carried out using Wood's intrinsic dissolution apparatus, and both drug and polymer release were quantified. ASDs at or below 25% DL showed rapid, complete, and congruent (i.e., simultaneous) release of the drug and polymer with dissolution rates similar to that of the polymer alone. The highest drug loading at which congruent release was observed is termed the limit of congruency (LoC) and occurred at 25% DL for RTV-PVPVA. The ASD with 30% DL showed an initial lag time, followed by a period of congruent release. At later times, the release of drug and polymer became incongruent with polymer releasing faster than drug. Higher DL ASDs (40 and 50%) showed slow release of both drug and polymer, whereby the drug release rate was similar to that of the neat amorphous drug. In cases where the release of the ASD components was congruent or close to congruent, the drug concentration exceeded the amorphous solubility, and liquid-liquid phase separation (LLPS) occurred with the formation of colloidal, drug-rich species. Solid state analyses of the ASD tablet surface by infrared spectroscopy and scanning electron microscopy revealed that the partially dissolved tablet surface remains smooth, and drug-polymer miscibility is retained at low DLs; whereas, at a very high DL, the surface is porous and enriched with amorphous drug. In concert, these observations suggest that ASD dissolution and drug release at low DLs is governed primarily by hydrophilic polymer; whereas, at high DLs, amorphous drug controls dissolution. Fluorescence microscopy images of thin ASD films suggested that ASDs at or below the LoC remain homogeneous even after exposure to water. In contrast ASDs with DL above LoC undergo, to various extents, water-induced amorphous-amorphous phase separation (AAPS) leading to demixing of the drug and polymer. Correlating the observations of the dissolution study with the solid state data suggest that the ASDs with DLs higher than the LoC undergo AAPS in the hydrating matrix on the surface of the dissolving solid during dissolution, leading to separation of drug and polymer, the formation of a drug-rich interface, and hence, incongruent and/or slow release of the components. In contrast, low DL ASDs dissolve before AAPS occurs. The competition between these two parallel and competing processes on the surface of ASD solids, i.e., dissolution and AAPS, thus dictates the overall release characteristics of the ASD formulations, which is one of the most important considerations in designing formulations with superior dissolution and absorption.

Mutual Impact of Phase Separation/Crystallization and Water Sorption in Amorphous Solid Dispersions.

The molecular integration of poorly water soluble active pharmaceutical ingredients (APIs) in a suitable polymeric matrix is a possible approach to enhance the dissolution behavior and solubility of these APIs. Like all newly developed pharmaceutical formulations, these formulations (often denoted as amorphous solid dispersions (ASDs)) need to undergo storage stability tests at defined relative humidity (RH) and temperature conditions. In a previous work ( Int. J. Pharm. 2017 ; 532 , 635 - 646 ), it was shown that thermodynamic modeling can be successfully used to predict the long-term stability of ASDs against API crystallization and moisture-induced amorphous-amorphous phase separation (MIAPS). This work in turn demonstrates the prediction of water sorption in ASDs accounting for the potential occurrence of API crystallization and MIAPS. The water sorption and phase behavior of ASDs containing the APIs felodipine and ibuprofen incorporated in three different hydrophilic polymers poly(vinylpyrrolidone), poly(vinyl acetate), and poly(vinylpyrrolidone-co-vinyl acetate) at the conditions 25 °C/60% RH and 40 °C/75% RH were predicted using the perturbed-chain statistical-associating fluid theory (PC-SAFT). The predictions were successfully validated via two-year-lasting water sorption experiments. It was shown that crystallization of the API and MIAPS on the one hand and water sorption in the ASDs on the other hand dramatically influence each other and that this behavior can even be quantitatively predicted by PC-SAFT, which already provides valuable insights at early stages of formulation development.

Phase Behavior of Ritonavir Amorphous Solid Dispersions during Hydration and Dissolution.

The aim of this research was to study the interplay of solid and solution state phase transformations during the dissolution of ritonavir (RTV) amorphous solid dispersions (ASDs). RTV ASDs with polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate (PVPVA) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) were prepared at 10-50% drug loading by solvent evaporation. The miscibility of RTV ASDs was studied before and after exposure to 97% relative humidity (RH). Non-sink dissolution studies were performed on fresh and moisture-exposed ASDs. RTV and polymer release were monitored using ultraviolet-visible spectroscopy. Techniques including fluorescence spectroscopy, confocal imaging, scanning electron microscopy (SEM), atomic force microscopy (AFM), differential scanning calorimetry (DSC) and nanoparticle tracking analysis (NTA) were utilized to monitor solid and the solution state phase transformations. All RTV-PVP and RTV-PVPVA ASDs underwent moisture-induced amorphous-amorphous phase separation (AAPS) on high RH storage whereas RTV-HPMCAS ASDs remained miscible. Non-sink dissolution of PVP- and PVPVA-based ASDs at low drug loadings led to rapid RTV and polymer release resulting in concentrations in excess of amorphous solubility, liquid-liquid phase separation (LLPS) and amorphous nanodroplet formation. High drug loading PVP- and PVPVA-based ASDs did not exhibit LLPS upon dissolution as a consequence of extensive AAPS in the hydrated ASD matrix. All RTV-HPMCAS ASDs led to LLPS upon dissolution. RTV ASD dissolution is governed by a competition between the dissolution rate and the rate of phase separation in the hydrated ASD matrix. LLPS was observed for ASDs where the drug release was polymer controlled and only ASDs that remained miscible during the initial phase of dissolution led to LLPS. Techniques such as fluorescence spectroscopy, confocal imaging and SEM were useful in understanding the phase behavior of ASDs upon hydration and dissolution and were helpful in elucidating the mechanism of generation of amorphous nanodroplets.

Melt Extrusion of High-Dose Co-Amorphous Drug-Drug Combinations : Theme: Formulation and Manufacturing of Solid Dosage Forms Guest Editors: Tony Zhou and Tonglei Li.

Many future drug products will be based on innovative manufacturing solutions, which will increase the need for a thorough understanding of the interplay between drug material properties and processability. In this study, hot melt extrusion of a drug-drug mixture with minimal amount of polymeric excipient was investigated. Using indomethacin-cimetidine as a model drug-drug system, processability of physical mixtures with and without 5% (w/w) of polyethylene oxide (PEO) were studied using Differential Scanning Calorimetry (DSC) and Small Amplitude Oscillatory Shear (SAOS) rheometry. Extrudates containing a co-amorphous glass solution were produced and the solid-state composition of these was studied with DSC. Rheological analysis indicated that the studied systems display viscosities higher than expected for small molecule melts and addition of PEO decreased the viscosity of the melt. Extrudates of indomethacin-cimetidine alone displayed amorphous-amorphous phase separation after 4weeks of storage, whereas no phase separation was observed during the 16week storage of the indomethacin-cimetidine extrudates containing 5% (w/w) PEO. Melt extrusion of co-amorphous extrudates with low amounts of polymer was found to be a feasible manufacturing technique. Addition of 5% (w/w) polymer reduced melt viscosity and prevented phase separation.

Understanding the process-product-performance interplay of spray dried drug-polymer systems through complete structural and chemical characterization of single spray dried particles

A complete description of the particle formation process can only be realized with techniques that enable the measurement of the composition and structural dependence of individual particles.The purpose of this publication is to highlight the utility of one such high resolution imaging technique; focused-ion scanning electron microscopy (FIB-SEM). As a model system, amorphous dispersion particles of felodipine and polyvinylpyrrolidone (PVP) were prepared by spray drying and used to interrogate single particles. Further, FIB-SEM was coupled with energy dispersive X-ray analysis (EDX) to characterize spatial chemical distributions in spray dried amorphous solid dispersion particles. Within a single spray drying batch, individual particles exhibited different phase behavior as a function of particle size. Larger particles showed notable amorphous-amorphous phase separation while smaller particles showed uniform composition. The morphology of particles was also found to be a function of particle size. Larger particles were consistently more porous in nature compared to smaller particles. The observed differences in compositional heterogeneity of different spray dried particles as a function of size are interpreted via theoretical arguments based on the Peclet number, the ratio of the evaporative flux of the solvent to the diffusive flux of the drug and the polymer within the droplet. Phase behavior may also be interpreted in terms of equilibrium ternary phase diagrams. Regardless, commonly used bulk physical and chemical characterization techniques may be used to establish correlations between the nature of the dispersion and the processing parameters. However, these techniques lack the resolution to provide a scientific link between the processing conditions and the nature of individual particles. The current paper highlights the utility of high resolution morphological and compositional measurements of individual particles.

Crystallization Kinetics of Indomethacin/Polyethylene Glycol Dispersions Containing High Drug Loadings.

The reproducibility and consistency of physicochemical properties and pharmaceutical performance are major concerns during preparation of solid dispersions. The crystallization kinetics of drug/polyethylene glycol solid dispersions, an important factor that is governed by the properties of both drug and polymer has not been adequately explored, especially in systems containing high drug loadings. In this paper, by using standard and modulated differential scanning calorimetry and X-ray powder diffraction, we describe the influence of drug loading on crystallization behavior of dispersions made up of indomethacin and polyethylene glycol 6000. Higher drug loading increases the amorphicity of the polymer and inhibits the crystallization of PEG. At 52% drug loading, polyethylene glycol was completely transformed to the amorphous state. To the best of our knowledge, this is the first detailed investigation of the solubilization effect of a low molecular weight drug on a semicrystalline polymer in their dispersions. In mixtures containing up to 55% indomethacin, the dispersions exhibited distinct glass transition events resulting from amorphous-amorphous phase separation which generates polymer-rich and drug-rich domains upon the solidification of supercooled polyethylene glycol, whereas samples containing at least 60% drug showed a single amorphous phase during the period in which crystallization normally occurs. The current study demonstrates a wide range in physicochemical properties of drug/polyethylene glycol solid dispersions as a result of the complex nature in crystallization of this system, which should be taken into account during preparation and storage.

Phase separation kinetics in amorphous solid dispersions upon exposure to water.

The purpose of this study was to develop a novel fluorescence technique employing environment-sensitive fluorescent probes to study phase separation kinetics in hydrated matrices of amorphous solid dispersions (ASDs) following storage at high humidity and during dissolution. The initial miscibility of the ASDs was confirmed using infrared (IR) spectroscopy and differential scanning calorimetry (DSC). Fluorescence spectroscopy, as an independent primary technique, was used together with conventional confirmatory techniques including DSC, X-ray diffraction (XRD), fluorescence microscopy, and IR spectroscopy to study phase separation phenomena. By monitoring the emission characteristics of the environment-sensitive fluorescent probes, it was possible to successfully monitor amorphous-amorphous phase separation (AAPS) as a function of time in probucol-poly(vinylpyrrolidone) (PVP) and ritonavir-PVP ASDs after exposure to water. In contrast, a ritonavir-hydroxypropylmethylcellulose acetate succinate (HPMCAS) ASD, did not show AAPS and was used as a control to demonstrate the capability of the newly developed fluorescence method to differentiate systems that showed no phase separation following exposure to water versus those that did. The results from the fluorescence studies were in good agreement with results obtained using various other complementary techniques. Thus, fluorescence spectroscopy can be utilized as a fast and efficient tool to detect and monitor the kinetics of phase transformations in amorphous solid dispersions during hydration and will help provide mechanistic insight into the stability and dissolution behavior of amorphous solid dispersions.

Optimization of a Raman Microscopy Technique to Efficiently Detect Amorphous–Amorphous Phase Separation in Freeze‐Dried Protein Formulations

A confocal Raman microscopic technique was optimized to more efficiently detect amorphous-amorphous phase separation in freeze-dried protein formulations. A Renishaw Raman inVia confocal microscope was used to collect 100-200 μm line maps (2 μm step size) of freeze-dried protein-excipient formulations. At each point across the line map, the composition was evaluated from the intensity of the nonoverlapping peaks representative of each component. Collection aperture, scan time, and line map length significantly contributed to the phase-separation analysis, whereas different sample preparation methods did not affect the analysis. Using the optimized parameters (i.e., large aperture 5 s scan time, 200 μm line map), phase separation was successfully detected in binary polymer formulations and was comparable to the previously developed Raman method. However, the previous method required 2.5 h/sample, whereas the optimized method only requires 0.5 h/sample. Phase separation was detected in the following protein-excipient formulations: lysozyme-trehalose (1:1), lysozyme-isomaltose (1:1), β-lactoglobulin-dextran (1:1), β-lactoglobulin-dextran (1:3), and β-lactoglobulin-trehalose (1:1). Phase separation was not detected in lysozyme-sucrose (1:1) and β-lactoglobulin-sucrose (1:1) formulations. The optimized method successfully detected phase separation in several protein formulations, where phase separation was previously suspected, and promised to be a useful tool for detection of phase separation in amorphous therapeutic formulations.