The Development of Minitablets for a Pediatric Dosage Form for a Combination Therapy.

Minitablets are an appealing option for an age-appropriate pediatric dosage form. In particular, for combination therapies where multiple active ingredients are dosed simultaneously, the use of minitablets will enable independent adjustments of each dose. The work presented describes the development of Compound A and Compound B minitablets for a combination therapy. Since both actives are formulated as spray dried amorphous solid dispersions (ASDs) due to low solubility of their crystalline forms, the choice of minitablets for the pediatric dosage form allows the application of the same formulation strategy across different age groups. To address the potential need for taste-masking, an ethylcellulose-hydroxypropyl cellulose coating system was developed. In-vitro performance testing was conducted to guide coating development and to ensure proper taste-masking without slowing down API dissolution in the GI tract that can negatively impact exposures. As a result, the exposure of orally dosed coated tablets was comparable to those of uncoated minitablets in the canine model. The work presented can serve as a case study on how minitablets can be designed and developed as an appropriate pediatric dosage form for a combination therapy comprised of ASD of active ingredients.

Producing Amorphous Solid Dispersions via Co-Precipitation and Spray Drying: Impact to Physicochemical and Biopharmaceutical Properties.

Many small-molecule active pharmaceutical ingredients (APIs) exhibit low aqueous solubility and benefit from generation of amorphous dispersions of the API and polymer to improve their dissolution properties. Spray drying and hot-melt extrusion are 2 common methods to produce these dispersions; however, for some systems, these approaches may not be optimal, and it would be beneficial to have an alternative route. Herein, amorphous solid dispersions of compound A, a low-solubility weak acid, and copovidone were made by conventional spray drying and co-precipitation. The physicochemical properties of the 2 materials were assessed via X-ray diffraction, differential scanning calorimetry, thermal gravimetric analysis, and scanning electron microscopy. The amorphous dispersions were then formulated and tableted, and the performance was assessed in vivo and in vitro. In human dissolution studies, the co-precipitation tablets had slightly slower dissolution than the spray-dried dispersion, but both reached full release of compound A. In canine in vitro dissolution studies, the tablets showed comparable dissolution profiles. Finally, canine pharmacokinetic studies showed that the materials had comparable values for the area under the curve, bioavailability, and Cmax. Based on the summarized data, we conclude that for some APIs, co-precipitation is a viable alternative to spray drying to make solid amorphous dispersions while maintaining desirable physicochemical and biopharmaceutical characteristics.

Amorphous Solid Dispersions or Prodrugs: Complementary Strategies to Increase Drug Absorption.

Maximizing oral bioavailability of drug candidates represents a challenge in the pharmaceutical industry. In recent years, there has been an increase in the use of amorphous solid dispersions (ASDs) to address this issue, where a growing number of solid dispersion formulations have been introduced to the market. However, an increase in solubility or dissolution rate through ASD does not always result in sufficient improvement of oral absorption because solubility limitations may still exist at high doses. Chemical modification in the form of a prodrug may offer an alternative approach for these cases. Although prodrugs have been primarily used to improve membrane permeability, examples are available in which prodrugs have been used to increase drug solubility beyond what can be achieved via formulation approaches. In this mini review, the role of ASDs and prodrugs as 2 complementary approaches in improving oral bioavailability of drug candidates is discussed. We discuss the fundamental principles of absorption and bioavailability, and review available literature on both solid dispersions and prodrugs, providing a summary of their use and examples of successful applications, and cover some of the biopharmaceutics evaluation aspects for these approaches.

Understanding the tendency of amorphous solid dispersions to undergo amorphous-amorphous phase separation in the presence of absorbed moisture.

Formulation of an amorphous solid dispersion (ASD) is one of the methods commonly considered to increase the bioavailability of a poorly water-soluble small-molecule active pharmaceutical ingredient (API). However, many factors have to be considered in designing an API-polymer system, including any potential changes to the physical stability of the API. In this study, the tendency of ASD systems containing a poorly water-soluble API and a polymer to undergo amorphous-amorphous phase separation was evaluated following exposure to moisture at increasing relative humidity. Infrared spectroscopy was used as the primary method to investigate the phase behavior of the systems. In general, it was observed that stronger drug-polymer interactions, low-ASD hygroscopicity, and a less hydrophobic API led to the formation of systems resistant to moisture-induced amorphous-amorphous phase separation. Orthogonal partial least squares analysis provided further insight into the systems, confirming the importance of the aforementioned properties. In order to design a more physically stable ASD that is resistant to moisture-induced amorphous-amorphous phase separation, it is important to consider the interplay between these properties.

Application of partial least-squares (PLS) modeling in quantifying drug crystallinity in amorphous solid dispersions.

Among the different experimental methods that can be used to quantify the evolution of drug crystallinity in polymer-containing amorphous solid dispersions, powder X-ray diffractometry (PXRD) is commonly considered as a frontline method. In order to achieve accurate quantification of the percent drug crystallinity in the system, calibration curves have to be constructed using appropriate calibration samples and calculation methods. This can be non-trivial in the case of partially crystalline solid dispersions where the calibration samples must capture the multiphase nature of the systems and the mathematical model must be robust enough to accommodate subtle and not so subtle changes in the diffractograms. The purpose of this study was to compare two different calculation and model-building methods to quantify the proportion of crystalline drug in amorphous solid dispersions containing different ratios of drug and amorphous polymer. The first method involves predicting the % drug crystallinity from the ratio of the area underneath the Bragg peaks to total area of the diffractogram. The second method is multivariate analysis using a Partial Least-Squares (PLS) multivariate regression method. It was found that PLS analysis provided far better accuracy and prediction of % drug crystallinity in the sample. Through the application of PLS, root-mean-squared error of estimation (RMSEE) values of 2.2%, 1.9%, and 4.7% drug crystallinity was achieved for samples containing 25%, 50%, and 75% polymer, respectively, compared to values of 11.2%, 17.0%, and 23.6% for the area model. In addition, construction of a PLS model enables further analysis of the data, including identification of outliers and non-linearity in the data, as well as insight into which factors are most important to correlate PXRD diffractograms with % crystallinity of the drug through analysis of the loadings.

Analysis of relationships between solid-state properties, counterion, and developability of pharmaceutical salts.

The solid-state properties of pharmaceutical salts, which are dependent on the counterion used to form the salt, are critical for successful development of a stable dosage form. In order to better understand the relationship between counterion and salt properties, 11 salts of procaine, which is a base, were synthesized and characterized using a variety of experimental and computational methods. Correlations between the various experimental and calculated physicochemical properties of the salts and counterions were probed. In addition to investigating the key factors affecting solubility, the hygroscopicity of the crystalline salts was studied to determine which solid-state and counterion properties might be responsible for enhancements in moisture uptake, thus providing the potential for adverse chemical stability. Multivariate principal components and partial least squares projection to latent structures analyses were performed in an attempt to establish predictive models capable of describing the relationships between these characteristics and both measured and calculated properties of the counterion and salt. Some success was achieved with respect to modeling crystalline salt solubility and the glass transition temperature of the amorphous salts. Through the modeling, insight into the relative importance of various descriptors on salt properties was achieved. The solid-state properties of crystalline and amorphous salts of procaine are highly dependent on the nature of the counterion. Important properties including aqueous solubility, melting point, hygroscopicity, and glass transition temperature were found to vary considerably between the different salts.

Effect of polymer hygroscopicity on the phase behavior of amorphous solid dispersions in the presence of moisture.

It has been previously observed that exposure to high relative humidity (RH) can induce amorphous-amorphous phase separation in solid dispersions composed of certain hydrophobic drugs and poly(vinylpyrrolidone) (PVP). The objective of this study was to investigate if this phenomenon occurred in solid dispersions prepared using less hygroscopic polymers. Drug-polymer miscibility was investigated before and after exposure to high RH using infrared (IR) spectroscopy and differential scanning calorimetry (DSC). PVP, poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA), and hypromellose acetate succinate (HPMCAS) were selected as model polymers, and felodipine, pimozide, indomethacin, and quinidine were selected as model drugs. Drug-polymer mixing at the molecular level was confirmed for all model systems investigated. Moisture-induced drug-polymer demixing was observed in felodipine-PVPVA, quinidine-PVP, quinidine-PVPVA, pimozide-PVPVA, and pimozide-HPMCAS systems, but was absent in the other HPMCAS dispersions and for indomethacin-PVPVA. It is concluded that the balance between the thermodynamic factors (enthalpy and entropy of mixing) in a ternary water-drug-polymer system is the important factor in determining which solid dispersion systems are susceptible to moisture-induced amorphous-amorphous phase separation. Systems with strong drug-polymer interactions and a less hygroscopic polymer will be less susceptible to moisture-induced phase separation, while more hydrophobic drugs will be more susceptible to this phenomenon even at low levels of sorbed moisture.

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.

Effects of polymer type and storage relative humidity on the kinetics of felodipine crystallization from amorphous solid dispersions.

PURPOSE: The objective of this study was to investigate the effects of polymer type and storage relative humidity (RH) on the crystallization kinetics of felodipine from amorphous solid dispersions. METHODS: Crystallization of the model drug felodipine from amorphous solid dispersion samples containing poly(vinyl pyrrolidone) (PVP) and hypromellose acetate succinate (HPMCAS) were evaluated. Samples at three different drug-polymer weight ratios (10, 25, and 50 wt. % polymer) were prepared and stored at six different RHs (0%, 32%, 52% or 66%, 75%, 86%, and 93%). Periodically, the fraction of the drug that had crystallized from the samples was quantified using powder X-ray diffractometry (PXRD). RESULTS: Felodipine crystallization rates from PVP-containing dispersions were found to be very sensitive to changes in storage RH, while crystallization rates from HPMCAS-containing dispersions were not. PVP and HPMCAS were similar in terms of their ability to inhibit crystallization at low RH, but when the storage RH was increased to 75% or above, felodipine crystallization from PVP-containing solid dispersions proceeded much faster. It is hypothesized that this trend was caused by moisture-induced drug-polymer immiscibility in PVP-felodipine system. For PVP-containing solid dispersion samples stored at 75% RH and above, crystallization of the model drug felodipine seemed to approach a kinetic plateau, whereby a fraction of the drug still remained amorphous even after storage for 500 days or more. CONCLUSIONS: The physical stability of solid dispersions as a function of RH is highly dependent on the polymer used to form the solid dispersion, with PVP-containing dispersions being much less physically stable at high RH than HPMCAS-containing dispersions.

Evaluation of drug-polymer miscibility in amorphous solid dispersion systems.

PURPOSE: To evaluate drug-polymer miscibility behavior in four different drug-polymer amorphous solid dispersion systems, namely felodipine-poly(vinyl pyrrolidone) (PVP), nifedipine-PVP, ketoconazole-PVP, and felodipine-poly(acrylic acid) (PAA). MATERIALS AND METHODS: Amorphous solid dispersion samples were prepared at different drug-to-polymer ratios and analyzed using differential scanning calorimetry (DSC), mid-infrared (IR) spectroscopy, and powder X-ray diffractometry (PXRD). To help with interpretation of the IR spectra, principal components (PC) analysis was performed. Pair Distribution Functions (PDFs) of the components in the dispersion were determined from the PXRD data, and the pure curves of the components were also extracted from PXRD data using the Pure Curve Resolution Method (PCRM) and compared against experimentally obtained results. RESULTS: Molecular-level mixing over the complete range of concentration was verified for nifedipine-PVP and felodipine-PVP. For felodipine-PAA, drug-polymer immiscibility was verified for samples containing 30 to 70% polymer, while IR results suggest at least some level of mixing for samples containing 10 and 90% polymer. For ketoconazole-PVP system, partial miscibility is suspected, whereby the presence of one-phase amorphous solid dispersion system could only be unambiguously verified at higher concentrations of polymer. CONCLUSIONS: The three techniques mentioned complement each other in establishing drug-polymer miscibility in amorphous solid dispersion systems. In particular, IR spectroscopy and PXRD are sensitive to changes in local chemical environments and local structure, which makes them especially useful in elucidating the nature of miscibility in binary mixtures when DSC results are inconclusive or variable.

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.

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.