Multicomponent Droplet Drying Modeling Based on Conservation and Population Balance Equations.

The aim of this work is to present a modeling tool to describe drying kinetics and delineate evolving physical and chemical behavior of multicomponent droplets during drying. Conservation equations coupled with population balance equations (PBE) are used to achieve this goal. Modeling results are gauged with single salt-water droplet drying from literature and show congruent trends. This model is then extended to a more complex system: various droplet sizes containing methanol (solvent), Felodipine (active ingredient), and PVP (polyvinylpyrrolidone as excipient). The FIB-SEM (Focused-Ion Beam Scanning Electron Microscopy) imaging results from spray-dried particles produced with similar formulation and processing conditions are consistent with phase behavior predicted by the model. The results show competing impacts of transport phenomena on the intermittent shell formation process and final particle structure and chemical heterogeneity. Solute diffusion, solvent efflux, and intra-drop flow impact the model system. It is found that shell formation follows a fluctuating profile where the initial precipitation of the dissolved species on the droplet surface is dampened, and nucleated particles become dispersed periodically until the shell becomes strong enough to withstand internal circulations. These internal effects are dependent on droplet size and are pronounced for larger droplets. That is, the particle phase behavior and physical nature are functions of the atomized droplet size. Stemming understating from this study would inform an optimized unit, operating in target design space. This would provide better product quality control and minimize discrepancies observed in process development during the early phase vs. commercial scale.

Mechanistic Investigation of Drug Supersaturation in the Presence of Polysorbates as Solubilizing Additives by Solution Nuclear Magnetic Resonance Spectroscopy.

The introduction of solubilizing additives has historically been an attractive approach to address the ever-growing proportion of poorly water-soluble drug (PWSD) compounds within the modern drug discovery pipeline. Lipid-formulations, and more specifically micelle formulations, have garnered particular interest because of their simplicity, size, scalability, and avoidance of solid-state limitations. Although micelle formulations have been widely utilized, the molecular mechanism of drug solubilization in surfactant micelles is still poorly understood. In this study, a series of modern nuclear magnetic resonance (NMR) methods are utilized to gain a molecular-level understanding of intermolecular interactions and kinetics in a model system. This approach enabled the understanding of how a PWSD, 17ß-Estradiol (E2), solubilizes within a nonionic micelle system composed of polysorbate 80 (PS80). Based on one-dimensional (1D) 1H chemical shift differences of E2 in PS80 solutions, as well as intermolecular correlations established from 1D selective nuclear Overhauser effect (NOE) and two-dimensional NOE spectroscopy experiments, E2 was found to accumulate within the palisade layer of PS80 micelles. A potential hydrogen-bonding interaction between a hydroxyl group of E2 and a carbonyl group of PS80 alkane chains may allow for stabilizing E2-PS80 mixed micelles. Diffusion and relaxation NMR analysis and particle size measurements using dynamic light scattering indicate a slight increase in the micellar size with increasing degrees of supersaturation, resulting in slower mobility of the drug molecule. Based on these structural findings, a theoretical orientation model of E2 molecules with PS80 molecules was developed and validated by computational docking simulations.

Approaches to Understanding the Solution-State Organization of Spray-Dried Dispersion Feed Solutions and Its Translation to the Solid State.

It is well established that polymers adopt a range of conformations and solution-state organization in response to varying solution environments, although very little work has been done to understand how these effects might impact the physical stability and bioavailability of spray-dried amorphous dispersions (SDDs). Potentially relevant solution-state polymer-solvent/cosolute interactions include preferential solvation, hydrodynamic size (i.e., polymer swelling or collapse), and solvent quality effects (i.e., attractive or repulsive self-interactions). Of particular interest is the investigation of preferential solvation, defined as the relative attraction or rejection of a cosolvent and/or cosolute from the local environment of a solvated macromolecule, which often occurs in multicomponent macromolecular solutions. As spray drying and other solvent-based dispersion processing necessitates the use of complex media consisting of at least three or more components (drug, polymer, solvent(s), and other possible excipients), the prevalence of this phenomenon is likely. This work characterizes largely unexplored solution-state properties in model spray-dried dispersion feed solutions using light scattering and viscometric techniques to add greater context and guidance in studying these information-rich materials. These systems are found to exhibit complex non-intuitive behavior, which serves to highlight the potential utility of preferential solvation in spray-dried dispersion processing and stability. It is hypothesized that solution-state organization of the liquid feed can be engineered and translated to the solid-state for the optimization of SDD properties.

Toward Developing Discriminating Dissolution Methods for Formulations Containing Nanoparticulates in Solution: The Impact of Particle Drift and Drug Activity in Solution.

Enabling formulations are an attractive approach to increase the dissolution rate, solubility, and oral bioavailability of poorly soluble compounds. With the growing prevalence of poorly soluble drug compounds in the pharmaceutical pipeline, supersaturating drug delivery systems (SDDS), a subset of enabling formulations, have grown in popularity due to their properties allowing for drug concentrations greater than the corresponding crystalline solubility. However, the extent of supersaturation generated as the enabling formulation traverses the gastrointestinal (GI) tract is dynamic and poorly understood. The dynamic nature of supersaturation is a result of several competing kinetic processes such as dissolution, solubilization by formulation and endogenous surfactants, crystallization, and absorption. Ultimately, the free drug concentration, which is equivalent to the drug's inherent thermodynamic activity amid these kinetic processes, defines the true driving force for drug absorption. However, in cases where solubilizing agents are present (i.e., surfactants and bile salts), drug molecules may associate with colloidal nanoscale species, complicating drug activity determination. These nanoscale species can drift into the aqueous boundary layer (ABL), increasing the local API activity at the membrane surface, resulting in increased bioavailability. Herein, a novel approach was developed to accurately measure thermodynamic drug activity in complex media containing drug distributed in nanoparticulate species. This approach captures the influence of the ABL on the observed flux and, ultimately, the predicted unbound drug concentration. The results demonstrate that this approach can help to (1) measure the true extent of local supersaturation in complex systems containing solubilizing excipients and (2) elucidate the mechanisms by which colloidal aggregates can modulate the drug activity in solution and potentially enhance the flux observed across a membrane. The utilization of these techniques may provide development scientists with a strategy to evaluate formulation sensitivity to nanospeciation and allow formulators to maximize the driving force for absorption in a complex environment, perhaps enabling the development of dissolution methods with greater discrimination and correlation to pre-clinical and clinical data sets.

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.

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, 15wt.% drug loading) and ezetimibe (EZT, 30wt.% 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 8days of storage at 40°C/82% RH, whereas no evidence of crystallinity could be observed by XRPD until 26days. Correspondingly, for FTM samples stored at 40°C/75% RH, crystals were detected after 11days by SHG microscopy and after 53days 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 (15days) with SHG microscopy relative to with XRPD (60days). 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.

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.

Solid-State Spectroscopic Investigation of Molecular Interactions between Clofazimine and Hypromellose Phthalate in Amorphous Solid Dispersions.

It has been technically challenging to specify the detailed molecular interactions and binding motif between drugs and polymeric inhibitors in the solid state. To further investigate drug-polymer interactions from a molecular perspective, a solid dispersion of clofazimine (CLF) and hypromellose phthalate (HPMCP), with reported superior amorphous drug loading capacity and physical stability, was selected as a model system. The CLF-HPMCP interactions in solid dispersions were investigated by various solid state spectroscopic methods including ultraviolet-visible (UV-vis), infrared (IR), and solid-state NMR (ssNMR) spectroscopy. Significant spectral changes suggest that protonated CLF is ionically bonded to the carboxylate from the phthalyl substituents of HPMCP. In addition, multivariate analysis of spectra was applied to optimize the concentration of polymeric inhibitor used to formulate the amorphous solid dispersions. Most interestingly, proton transfer between CLF and carboxylic acid was experimentally investigated from 2D 1H-1H homonuclear double quantum NMR spectra by utilizing the ultrafast magic-angle spinning (MAS) technique. The molecular interaction pattern and the critical bonding structure in CLF-HPMCP dispersions were further delineated by successfully correlating ssNMR findings with quantum chemistry calculations. These high-resolution investigations provide critical structural information on active pharmaceutical ingredient-polymer interaction, which can be useful for rational selection of appropriate polymeric carriers, which are effective crystallization inhibitors for amorphous drugs.

Impact of Metallic Stearates on Disproportionation of Hydrochloride Salts of Weak Bases in Solid-State Formulations.

Excipient-induced salt disproportionation (conversion from salt form to free form) in the solid state during storage or manufacturing is a severe formulation issue that can negatively influence product performance. However, the role of excipient properties on salt disproportionation and mechanisms of proton transfer between salt and excipients are still unclear. Moreover, knowledge about the formation of disproportionation products and the consequent impact of these reactions products on the disproportionation process is still inadequate. In the present study, three commonly used lubricants (sodium stearate, calcium stearate, and magnesium stearate) were mixed with a hydrochloride salt as binary mixtures to examine their different capabilities for inducing salt disproportionation at a stressed storage condition (40 °C/65% RH). The overall objective of this research is to explore factors influencing the kinetics and extent of disproportionation including surface area, alkalinity, hygroscopicity, formation of new species, etc. In addition, we also aim to clarify the reaction mechanism and proton transfer between the model salt and stearates to provide insight into the in situ formed reaction products. We found that the properties of stearates significantly affect the disproportionation process in the initial stage of storage, while properties of the reaction products negatively affect the hygroscopicity of the powder mixture promoting disproportionation during longer-term storage. In addition, lubrication difference among three stearates was evaluated by performing compaction studies. The findings of this study provide an improved understanding of the proton transfer mechanism between the ionized form of an active pharmaceutical ingredient and excipients in solid dosage forms. It also provides pragmatic information for formulation scientists to select appropriate lubricants and other excipients, and to design robust formulations.

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.

Size selectivity of intestinal mucus to diffusing particulates is dependent on surface chemistry and exposure to lipids.

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.

Multicomponent chemical imaging of pharmaceutical solid dosage forms with broadband CARS microscopy.

We compare a coherent Raman imaging modality, broadband coherent anti-Stokes Raman scattering (BCARS) microscopy, with spontaneous Raman microscopy for quantitative and qualitative assessment of multicomponent pharmaceuticals. Indomethacin was used as a model active pharmaceutical ingredient (API) and was analyzed in a tabulated solid dosage form, embedded within commonly used excipients. In comparison with wide-field spontaneous Raman chemical imaging, BCARS acquired images 10× faster, at higher spatiochemical resolution and with spectra of much higher SNR, eliminating the need for multivariate methods to identify chemical components. The significant increase in spatiochemical resolution allowed identification of an unanticipated API phase that was missed by the spontaneous wide-field method and bulk Raman spectroscopy. We confirmed the presence of the unanticipated API phase using confocal spontaneous Raman, which provided spatiochemical resolution similar to BCARS but at 100× slower acquisition times.

Effect of temperature and moisture on the miscibility of amorphous dispersions of felodipine and poly(vinyl pyrrolidone).

The physical stability of amorphous molecular level solid dispersions will be influenced by the miscibility of the components. The goal of this work was to understand the effects of temperature and relative humidity on the miscibility of a model amorphous solid dispersion. Infrared spectroscopy was used to evaluate drug-polymer hydrogen bonding interactions in amorphous solid dispersions of felodipine and poly(vinyl pyrrolidone) (PVP). Samples were analyzed under stressed conditions: high temperature and high relative humidity. The glass transition temperature (T(g)) of select systems was studied using differential scanning calorimetry (DSC). Atomic force microscopy (AFM) and transmission electron microscopy (TEM) were used to further investigate moisture-induced changes in solid dispersions. Felodipine-PVP solid dispersions showed evidence of adhesive hydrogen bonding interactions at all compositions studied. The drug-polymer intermolecular interactions were weakened and/or less numerous on increasing the temperature, but persisted up to the melting temperature of the drug. Changes in the hydrogen bonding interactions were found to be reversible with changes in temperature. In contrast, the introduction of water into amorphous molecular level solid dispersions at room temperature irreversibly disrupted interactions between the drug and the polymer resulting in amorphous-amorphous phase separation followed by crystallization. DSC, AFM, and TEM results provided further evidence for the occurrence of moisture induced immiscibility. In conclusion, it appears that felodipine-PVP solid dispersions are susceptible to moisture-induced immiscibility when stored at a relative humidity >or=75%. In contrast, the solid dispersions remained miscible on heating.

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.

Estimation of drug-polymer miscibility and solubility in amorphous solid dispersions using experimentally determined interaction parameters.

PURPOSE: The amorphous form of a drug may provide enhanced solubility, dissolution rate, and bioavailability but will also potentially crystallize over time. Miscible polymeric additives provide a means to increase physical stability. Understanding the miscibility of drug-polymer systems is of interest to optimize the formulation of such systems. The purpose of this work was to develop experimental models which allow for more quantitative estimates of the thermodynamics of mixing amorphous drugs with glassy polymers. MATERIALS AND METHODS: The thermodynamics of mixing several amorphous drugs with amorphous polymers was estimated by coupling solution theory with experimental data. The entropy of mixing was estimated using Flory-Huggins lattice theory. The enthalpy of mixing and any deviations from the entropy as predicted by Flory-Huggins lattice theory were estimated using two separate experimental techniques; (1) melting point depression of the crystalline drug in the presence of the amorphous polymer was measured using differential scanning calorimetry and (2) determination of the solubility of the drug in 1-ethyl-2-pyrrolidone. The estimated activity coefficient was used to calculate the free energy of mixing of the drugs in the polymers and the corresponding solubility. RESULTS: Mixtures previously reported as miscible showed various degrees of melting point depression while systems reported as immiscible or partially miscible showed little or no melting point depression. The solubility of several compounds in 1-ethyl-2-pyrrolidone predicts that most drugs have a rather low solubility in poly(vinylpyrrolidone). CONCLUSIONS: Miscibility of various drugs with polymers can be explored by coupling solution theories with experimental data. These approximations provide insight into the physical stability of drug-polymer mixtures and the thermodynamic driving force for crystallization.

Development of a rapidly dispersing tablet of a poorly wettable compound: formulation DOE and mechanistic study of effect of formulation excipients on wetting of celecoxib.

Celecoxib has extremely poor aqueous wettability and dispersibility. A dispersibility method was developed to study the effects of formulation excipients and processing methods on wetting of celecoxib. In this method, a tablet or powder was placed in water and the turbidity of the resulting "dynamic" suspension was measured. Higher turbidity values reflect better dispersibility. Results show that wet granulation facilitates better drug dispersion than does dry granulation or direct compression. Results from a screening formulation statistical design of experiments (DOE) show that sodium lauryl sulfate (SLS), an anionic surfactant, gives higher celecoxib dispersibility than polysorbate 80, a neutral surfactant. Polyplasdone XL as a disintegrant results in better celecoxib dispersibility than sodium starch glycolate. The binder Kollidon 30 leads to better dispersibility, but slower disintegration than Kollidon 12. Jet-milling celecoxib with excipients not only improves dispersibility of the drug but also the ease of material handling. The method of microcrystalline cellulose addition does not significantly impact tablet properties. The effect of critical formulation variables on the wettability of celecoxib was further examined in prototype formulations. It is found that ionic surfactant resulted in better dispersibility than a neutral surfactant, probably due to charge dispersion. Kollidon 30 gives better drug dispersion than hydroxypropylmethyl cellulose and hydroxypropyl cellulose. This may be explained through a surface energy calculation, where the spreading coefficients between Kollidon 30 and celecoxib indicate formation of open porous granules in which pores can facilitate water uptake. The mode of disintegrant addition also impacts dispersibility of the drug. Dense granules were formed when the disintegrant, Polyplasdone, was added intra-granularly. As the extra-granular portion of the disintegrant increases, the dispersibility of the drug increases as well. The drug initial dispersibility (turbidity at 5 min during the dispersibility test) increases as the tablet porosity increases. A 3-factor face-centered experimental design was conducted to optimize the levels of surfactant (SLS), binder (Kollidon 30) and disintegrant (Polyplasdone). Within the range that was studied, the dispersibility of micronized drug increases as the amount of SLS and Kollidon 30 increases. The level of Polyplasdone has no significant impact on the dispersibility of micronized drug; however, higher levels of Polyplasdone lead to significantly harder tablets.

Spontaneous crystallinity loss of drugs in the disordered regions of poly(ethylene oxide) in the presence of water.

The physical stability of active pharmaceutical ingredients (APIs) formulated in the crystalline state may be compromised in the presence of excipients. In the present study, it is shown that at high relative humidity, several model crystalline drugs compacted into a matrix of poly(ethylene oxide) (PEO) may dissolve into the disordered regions of the polymer. The purpose of this project is to identify both the physicochemical properties of the API and the polymer which may lead to such a transformation and the mechanism of transformation. Crystalline drugs and PEO were physically mixed, compressed into tablets, and stored in a dessicator at 94% RH. The physical state of the drug and the polymer were determined using Raman spectroscopy and X-ray powder diffraction. The solubility of each drug in PEG 400 was measured by ultraviolet spectroscopy, the thermal properties of each compound were measured using differential scanning calorimetry, and the amount of water sorbed into these systems from the vapor phase was determined by gravimetric analysis. A spontaneous loss of crystallinity was observed for many of the model drugs when stored at high relative humidity and in the presence of PEO. In the absence of PEO, no changes in the crystalline material were observed. However, the structure of PEO was dramatically altered when exposed to high relative humidity. Specifically, it was found that PEO undergoes a very slow deliquescence increasing the disordered fraction of the polymer which facilitates the "dissolution" of the crystalline drug into these disordered regions. The degree of transformation, estimated from Raman spectroscopy, was found to qualitatively correlate with the aqueous solubility of the compounds. It can be concluded that for the systems studied here, the phase stability of the polymer was compromised at high relative humidity and the polymer underwent deliquescence. The equilibrium phase of several of the crystalline drugs studied here was then altered as evidenced by a loss in crystallinity.

Recrystallization of nifedipine and felodipine from amorphous molecular level solid dispersions containing poly(vinylpyrrolidone) and sorbed water.

PURPOSE: To compare the physical stability of amorphous molecular level solid dispersions of nifedipine and felodipine, in the presence of poly(vinylpyrrolidone) (PVP) and small amounts of moisture. METHODS: Thin amorphous films of nifedipine and felodipine and amorphous molecular level solid dispersions with PVP were stored at various relative humidities (RH) and the nucleation rate was measured. The amount of water sorbed at each RH was measured using isothermal vapor sorption and glass transition temperatures (Tg) were determined using differential scanning calorimetry. The solubility of each compound in methyl pyrrolidone was measured as a function of water content. RESULTS: Nifedipine crystallizes more easily than felodipine at any given polymer concentration and in the presence of moisture. The glass transition temperatures of each compound, alone and in the presence of PVP, are statistically equivalent at any given water content. The nifedipine systems are significantly more hygroscopic than the corresponding felodipine systems. CONCLUSIONS: Variations in the physical stability of the two compounds could not be explained by differences in Tg. However, the relative physical stability is consistent with differences in the degree of supersaturation of each drug in the solid dispersion, treating the polymer and water as a co-solvent system for each drug compound.

A comparison of the physical stability of amorphous felodipine and nifedipine systems.

PURPOSE: The objective of this study was to investigate thermodynamic and kinetic factors contributing to differences in the isothermal nucleation rates of two structurally related calcium channel blockers, nifedipine and felodipine, both alone and in the presence of poly(vinylpyrrolidone) (PVP). MATERIALS AND METHODS: Thin films of amorphous systems were cast onto glass slides and the nucleation rate was determined using optical microscopy. Enthalpy, entropy, and free energy of crystallization of the pure compounds were measured using differential scanning calorimetery (DSC). Molecular mobility and glass transition temperature of each amorphous system were characterized using DSC and hydrogen bonding patterns were analyzed with infrared spectroscopy. The composition dependence of the thermodynamic activity of the amorphous drug in the presence of the polymer was estimated using Flory-Huggins lattice theory. RESULTS: Nifedipine crystallized more readily than felodipine from the metastable amorphous form both alone and in the presence of PVP despite having a similar glass transition temperature and molecular mobility. Nifedipine was found to have a larger enthalpic driving force for crystallization and a lower activation energy for nucleation. CONCLUSIONS: The properties of the metastable form alone did not explain the greater propensity for nifedipine crystallization. When considering the physical stability of amorphous systems, it is important to also consider the properties of the crystalline counterpart.

Theoretical and practical approaches for prediction of drug-polymer miscibility and solubility.

PURPOSE: Crystallization of drugs formulated in the amorphous form may lead to reduced apparent solubility, decreased rate of dissolution and bioavailability and compromise the physical integrity of the solid dosage form. The purpose of this work was to develop thermodynamic approaches, both practical and theoretical, that will yield a better understanding of which factors are most important for determining the ability of polymers to stabilize amorphous active pharmaceutical ingredients (API). MATERIALS AND METHODS: Lattice based solution models were used to examine miscibility criteria in API-polymer blends. Different methods were used to estimate the Flory-Huggins interaction parameter for model API-polymer systems consisting of felodipine or nifedipine with poly(vinylpyrrolidone) (PVP). These were melting point depression and determination of solubility parameters using group contribution theory. The temperature and enthalpy of fusion of crystalline API alone and the fusion temperature of the API in the presence of the polymer were measured by differential scanning calorimetry. The resultant thermal data were used to estimate the reduced driving force for crystallization and the solubility of the API in the polymer. RESULTS: Flory-Huggins theory predicts that, for typical API-polymer systems, the entropy of mixing is always favorable and should be relatively constant. Due to the favorable entropy of mixing, miscibility can still be achieved in systems with a certain extent of unfavorable enthalpic interactions. For the model systems, interaction parameters derived from melting point depression were negative indicating that mixing was exothermic. Using these interaction parameters and Flory-Huggins theory, miscibility was predicted for all compositions, in agreement with experimental data. A model was developed to estimate the solubility of the API in the polymer. The estimated solubility of the model APIs in PVP is low suggesting that kinetic rather than thermodynamic stabilization plays a significant role in inhibiting crystallization. CONCLUSIONS: The thermodynamics of API-polymer systems can be modeled using solution based theories. Such models can contribute towards providing an understanding of the compatibility between API and polymer and the mechanisms of physical stabilization in such systems.