Understanding the Influence of API Conformations on Amorphous Dispersion Formation Potential Predictions using the R3m Molecular Descriptor.

The R3m molecular descriptor (R-GETAWAY third-order autocorrelation index weighted by the atomic mass) has previously been shown to encode molecular attributes that appear to be physically and chemically relevant to grouping diverse active pharmaceutical ingredients (API) according to their potential to form persistent amorphous solid dispersions (ASDs) with polyvinylpyrrolidone-vinyl acetate copolymer (PVPVA). The initial R3m dispersibility model was built by using a single three-dimensional (3D) conformation for each drug molecule. Since molecules in the amorphous state will adopt a distribution of conformations, molecular dynamics simulations were performed to sample conformations that are probable in the amorphous form, which resulted in a distribution of R3m values for each API. Although different conformations displayed R3m values that differed by as much as 0.4, the median of each R3m distribution and the value predicted from the single 3D conformation were very similar for most structures studied. The variability in R3m resulting from the distribution of conformations was incorporated into a logistic regression model for the prediction of ASD formation in PVPVA, which resulted in a refinement of the classification boundary relative to the model that only incorporated a single conformation of each API.

Effect of Structurally Related Compounds on Desupersaturation Kinetics of Indomethacin.

PURPOSE: The pharmaceutical literature contains examples wherein desupersaturation from high concentrations does not proceed to equilibrium concentration of the thermodynamically most stable form but remains above equilibrium. The purpose of the current research was to investigate the effect of structurally related compounds on desupersaturation kinetics as a possible explanation for a higher than equilibrium solubility after crystal growth of γ-indomethacin (γ-IMC). METHODS: Three structurally related compounds (SRC) - cis-sulindac (c-SUL), trans-sulindac (t-SUL) and indomethacin-related compound-A (IMC-A) -were investigated. Desupersaturation kinetics to the most stable γ-IMC, in the presence of c-SUL, t-SUL or IMC-A, was measured at pH 2.0. RESULTS: The SRCs c-SUL and t-SUL were effective crystallization inhibitors of IMC, while IMC-A was not a potent crystallization inhibitor of IMC. Among the sulindac isomers, t-SUL was a stronger crystallization inhibitor. The apparent solubility of γ-IMC crystals grown from supersaturated solutions in the presence of SRCs matched the equilibrium solubility of γ-IMC. During crystallization of IMC in the presence of IMC-A, the concentration of IMC-A declined initially but rebounded as supersaturation and crystallization rate of IMC declined, suggesting that IMC-A itself became incorporated in the IMC crystal lattice at higher degrees of IMC supersaturation. CONCLUSIONS: The results suggest that high apparent solubility after crystallization of IMC reported by several authors is not related to the presence of IMC-A impurity. The greater IMC crystal growth rate inhibition by t-SUL than by c-SUL was consistent with the proposed orientation of SUL molecules adsorbed on the IMC crystal, providing a mechanistic understanding of the inhibition.

Re-visitation of Two Models for Predicting Mechanically-Induced Disordering after Cryogenic Impact Milling.

PURPOSE: To compare the prediction accuracy of two models used to characterize the complete disordering potential of materials after extensive cryogenic milling. METHODS: Elastic shear moduli (µs) were simulated in silico. Comparison with available literature values confirmed that computations were reasonable. Complete disordering potential was predicted using the critical dislocation density (ρcrit) and bivariate empirical models. To compare the prediction accuracy of the models, each material added for dataset expansion was cryomilled for up to 5 hr. Mechanical disordering after comminution was characterized using PXRD and DSC, and pooled with previously published results. RESULTS: Simulated µs enabled predictions using the ρcrit model for 29 materials. This model mischaracterized the complete disordering behavior for 13/29 materials, giving an overall prediction accuracy of 55%. The originally published bivariate empirical model classification boundary correctly grouped the disordering potential for 31/32 materials from the expanded dataset. Recalibration of this model retained a 94% prediction accuracy, with only 2 misclassifications. CONCLUSIONS: Prediction accuracy of the ρcrit model decreased with dataset expansion, relative to previously published results. Overall, the ρcrit model was considerably less accurate relative to the bivariate empirical model, which retained very high prediction accuracy for the expanded dataset. Although the empirical model does not imply a mechanism, model robustness suggests the importance of glass transition temperature (Tg) and molar volume (Mv) on formation and persistence of amorphous materials following extensive cryomilling.

The Implications of Drug-Polymer Interactions on the Physical Stability of Amorphous Solid Dispersions.

Amorphous solid dispersions (ASDs) are a formulation and development strategy that can be used to increase the apparent aqueous solubility of poorly water-soluble drugs. Their implementation, however, can be hindered by destabilization of the amorphous form, as the drug recrystallizes from its metastable state. Factors such as the drug-polymer solubility, miscibility, mobility, and nucleation/crystal growth rates are all known to impact the physical stability of an ASD. Non-covalent interactions (NCI) between the drug and polymer have also been widely reported to influence product shelf-life. In this review, the relationship between thermodynamic/kinetic factors and adhesive NCI is assessed. Various types of NCIs reported to stabilize ASDs are described, and their role in affecting physical stability is examined. Finally, NCIs that have not yet been widely explored in ASD formulations, but may potentially impact their physical stability are also briefly described. This review aims to stimulate further theoretical and practical exploration of various NCIs and their applications in ASD formulations in the future.

Investigating and Comparing the Applicability of the R3m Molecular Descriptor and Solubility Parameter Estimation Approaches in Predicting Dispersion Formation Potential of APIs in a Random Co-Polymer Polyvinylpyrrolidone Vinyl Acetate and its Homopolymer.

Evaluation of different amorphous solid dispersion carrier matrices is enabled by active pharmaceutical ingredient (API) structure-based predictions. This study compares the utility of Hansen Solubility Parameters with the R3m molecular descriptor for identifying dispersion polymers based on the structure of the drug molecule. Twelve API-polymer combinations (4 APIs and 3 interrelated polymers) were used to test each approach. Co-solidified mixtures containing 75% API were prepared by melt-quenching. Phase behavior was evaluated and classified using differential scanning calorimetry, powder X-ray diffraction, polarized light microscopy, and hot stage microscopy. Observations of dispersion behavior were compared to predictions made using the Hansen Solubility Parameter and R3m. The solubility parameter approach misclassified the dispersion behavior of 1 API-polymer combination and also did not produce definite predictions in 3 out of 12 of the API-polymer combinations. In contrast, R3m classifications of dispersion behavior were correct in all but two cases, with one misclassification and one ambiguous prediction. The solubility parameters best classify dispersion behavior when specific drug-polymer intermolecular interactions are present, but may be less useful otherwise. Ultimately, these two methods are most effectively used together, as they are based on distinct features of the same molecular structure.

Implications of Coexistent Halogen and Hydrogen Bonds in Amorphous Solid Dispersions on Drug Solubility, Miscibility, and Mobility.

Specific noncovalent drug-polymer interactions were analytically identified using Raman and Fourier transform infrared spectroscopy for amorphous solid dispersions (ASD) formed between either chlorpropamide or tolbutamide and polyvinylpyrrolidone vinyl acetate random copolymer (PVPVA). Spectral changes in the C-Cl stretching vibrations due to changes in the electronic environment of the Cl atom confirmed halogen bond formation in chlorpropamide-PVPVA ASDs, the extent of which was established to be inversely related to the concentration of the drug using 2D correlation spectroscopy analysis. Hydrogen bonding between the secondary amide of each drug and the pyrrolidone carbonyl of the copolymer was also confirmed in all dispersions. Implications of coexistent interactions were investigated for drug-polymer solubility, mixing free energy, and molecular mobility relative to tolbutamide, which only formed hydrogen bonds with PVPVA. Chlorpropamide had a higher solubility, a larger negative mixing free energy, and lower mobility in PVPVA relative to tolbutamide. These thermodynamic and kinetic differences demonstrate the significance of halogen bond formation even when hydrogen bonding is present.

Crystal structure of 4-bromo-N-(propyl-carbamo-yl)benzene-sulfonamide.

The title compound, C10H13BrN2O3S, 1, contains a sulfonyl urea moiety, which possesses potential therapeutic functions (e.g., anti-diabetic and herbicidal). The geometry of 1 is similar to its closely related analogues, chlorpropamide and tolbutamide. This compound crystallizes in the monoclinic space group C2/c, having one mol-ecule in its asymmetric unit. The crystal structure of 1, recorded at 296 K, shows inter-molecular N-H⋯O and C-H⋯O-type infinite hydrogen-bonded chains involving the sulfonyl urea moiety. Hirshfeld surface analysis and the two-dimensional fingerprint plots confirmed hydrogen bonding as the dominant feature in the crystal packing.

Interpreting the Physicochemical Meaning of a Molecular Descriptor Which Is Predictive of Amorphous Solid Dispersion Formation in Polyvinylpyrrolidone Vinyl Acetate.

A molecular descriptor known as R3m (the R-GETAWAY third-order autocorrelation index weighted by the atomic mass) was previously identified as capable of grouping members of an 18-compound library of organic molecules that successfully formed amorphous solid dispersions (ASDs) when co-solidified with the co-polymer polyvinylpyrrolidone vinyl acetate (PVPva) at two concentrations using two preparation methods. To clarify the physical meaning of this descriptor, the R3m calculation is examined in the context of the physicochemical mechanisms of dispersion formation. The R3m equation explicitly captures information about molecular topology, atomic leverage, and molecular geometry, features which might be expected to affect the formation of stabilizing non-covalent interactions with a carrier polymer, as well as the molecular mobility of the active pharmaceutical ingredient (API) molecule. Molecules with larger R3m values tend to have more atoms, especially the heavier ones that form stronger non-covalent interactions, generally, more irregular shapes, and more complicated topology. Accordingly, these molecules are more likely to remain dispersed within PVPva. Furthermore, multiple linear regression modeling of R3m and more interpretable descriptors supported these conclusions. Finally, the utility of the R3m descriptor for predicting the formation of ASDs in PVPva was tested by analyzing the commercially available products that contain amorphous APIs dispersed in the same polymer. All of these analyses support the conclusion that the information about the API geometry, size, shape, and topological connectivity captured by R3m relates to the ability of a molecule to interact with and remain dispersed within an amorphous PVPva matrix.

Evaluation of Ribavirin-Poloxamer Microparticles for Improved Intranasal Absorption.

Ribavirin is a water-soluble antiviral compound which, owing to its inability to cross the blood-brain barrier, has limited effectiveness in treating viruses affecting the central nervous system. Direct nose-to-brain delivery was investigated for ribavirin in combination with poloxamer 188, an excipient known to enhance the absorption of drug compounds administered intranasally. Composite solid microparticles suitable for intranasal insufflation were prepared by suspending fine crystals of ribavirin in a matrix of poloxamer 188, which were cryogenically milled and characterized to ensure that ribavirin remained stable throughout preparation. In vitro diffusion of ribavirin across a semi-permeable regenerated cellulose membrane showed comparable cumulative drug release after 180 min from both fine solid particles (<20 µm) and 1:1 ribavirin:poloxamer microparticles (d50 = 20 µm); however, the initial release from polymer microparticles was slower, owing to gel formation on the membrane surface. When solid ribavirin was directly deposited on excised olfactory mucosa, either as fine drug particles or 1:1 ribavirin:poloxamer microparticles, permeation was significantly increased from microparticles containing poloxamer 188, suggesting additional interactions between the polymer and olfactory mucosa. These data indicate that for highly water-soluble drugs such as ribavirin or drugs subject to efflux by the nasal mucosa, a formulation of poloxmer-containing microparticles can enhance permeability across the olfactory epithelium and may improve direct nose-to-brain transport.

Crystal structure of tert-butyl 4-[4-(4-fluoro-phen-yl)-2-methyl-but-3-yn-2-yl]piperazine-1-carboxyl-ate.

The title sterically congested piperazine derivative, C20H27FN2O2, was prepared using a modified Bruylants approach. A search of the Cambridge Structural Database identified 51 compounds possessing an N-tert-butyl piperazine substructure. Of these only 14 were asymmetrically substituted on the piperazine ring and none with a synthetically useful second nitro-gen. Given the novel chemistry generating a pharmacologically useful core, determination of the crystal structure for this compound was necessary. The piperazine ring is present in a chair conformation with di-equatorial substitution. Of the two N atoms, one is sp 3 hybridized while the other is sp 2 hybridized. Inter-molecular inter-actions resulting from the crystal packing patterns were investigated using Hirshfeld surface analysis and fingerprint analysis. Directional weak hydrogen-bond-like inter-actions (C-H⋯O) and C-H⋯π inter-actions with the dispersion inter-actions as the major source of attraction are present in the crystal packing.

Predicting Density of Amorphous Solid Materials Using Molecular Dynamics Simulation.

The true density of an amorphous solid is an important parameter for studying and modeling materials behavior. Experimental measurements of density using helium pycnometry are standard but may be prevented if the material is prone to rapid recrystallization, or preparation of gram quantities of reproducible pure component amorphous materials proves impossible. The density of an amorphous solid can be approximated by assuming it to be 95% of its respective crystallographic density; however, this can be inaccurate or impossible if the crystal structure is unknown. Molecular dynamic simulations were used to predict the density of 20 amorphous solid materials. The calculated density values for 10 amorphous solids were compared with densities that were experimentally determined using helium pycnometry. In these cases, the amorphous densities calculated using molecular dynamics had an average percent error of - 0.7% relative to the measured values, with a maximum error of - 3.48%. In contrast, comparisons of amorphous density approximated from crystallographic structures with pycnometrically measured values resulted in an average percent error of + 3.7%, with a maximum error of + 9.42%. These data suggest that the density of an amorphous solid can be accurately predicted using molecular dynamic simulations and allowed reliable calculation of density for the remaining 10 materials for which pycnometry could not be done.

Differential scanning calorimetry isothermal hold times can impact interpretations of drug-polymer dispersability in amorphous solid dispersions.

Differential scanning calorimetry (DSC) is a commonly employed analytical technique for the analysis and characterization of amorphous solid dispersions. However, steps typical of standard temperature programs can alter the material in situ. Data for two active pharmaceutical ingredients are detailed, wherein isothermal hold times, traditionally employed to remove thermal history and/or residual solvent, were observed to impact the observed dispersability of the compounds in polyvinylpyrrolidone vinyl-acetate copolymer (PVPva). Re-crystallized tolbutamide was observed to re-dissolve in PVPva, while terfenadine was observed to crystallize during the isothermal hold period. Exposing co-solidified drug-polymer mixtures to temperature changes and experimental hold times can potentially confound correct categorization of dispersability, particularly when DSC is used as the lone characterization technique. This work illustrates the importance of using a combination of techniques to improve the certainty of conclusions made with respect to the true, initial physical state of a co-solidified mixture.

The Application of Modeling and Prediction to the Formation and Stability of Amorphous Solid Dispersions.

Amorphous solid dispersion (ASD) formulation development is frequently difficult owing to the inherent physical instability of the amorphous form, and limited understanding of the physical and chemical interactions that translate to initial dispersion formation and long-term physical stability. Formulation development for ASDs has been historically accomplished through trial and error or experience with extant systems; however, rational selection of appropriate excipients is preferred to reduce time to market and decrease costs associated with development. Current efforts to develop thermodynamic and computational models attempt to rationally direct formulation and show promise. This review compiles and evaluates important methods used to predict ASD formation and physical stability. Recent literature in which these methods are applied is also reviewed, and limitations of each method are discussed.

Modeling and Prediction of Drug Dispersability in Polyvinylpyrrolidone-Vinyl Acetate Copolymer Using a Molecular Descriptor.

The expansion of a novel in silico model for the prediction of the dispersability of 18 model compounds with polyvinylpyrrolidone-vinyl acetate copolymer is described. The molecular descriptor R3m (atomic mass weighted 3rd-order autocorrelation index) is shown to be predictive of the formation of amorphous solid dispersions at 2 drug loadings (15% and 75% w/w) using 2 preparation methods (melt quenching and solvent evaporation using a rotary evaporator). Cosolidified samples were characterized using a suite of analytical techniques, which included differential scanning calorimetry, powder X-ray diffraction, pair distribution function analysis, polarized light microscopy, and hot stage microscopy. Logistic regression was applied, where appropriate, to model the success and failure of compound dispersability in polyvinylpyrrolidone-vinyl acetate copolymer. R3m had combined prediction accuracy greater than 90% for tested samples. The usefulness of this descriptor appears to be associated with the presence of heavy atoms in the molecular structure of the active pharmaceutical ingredient, and their location with respect to the geometric center of the molecule. Given the higher electronegativity and atomic volume of these types of atoms, it is hypothesized that they may impact the molecular mobility of the active pharmaceutical ingredient, or increase the likelihood of forming nonbonding interactions with the carrier polymer.

Solid-state transformations of ribavirin as a result of high-shear mechanical processing.

Ribavirin (C8H12N4O5; anti-viral agent) was crystallized as two unique, phase-pure polymorphs (R-I and R-II). Calorimetrically determined isobaric heat capacities and heat of transition data were utilized to determine the solid-state transition temperature (Ttr), confirming enantiotropism, while R-I was determined to be kinetically stable at ambient temperature. Unprocessed samples of the low Tm polymorph, R-II, did not convert into R-I when held isothermally well above Ttr for 7days. In contrast milled R-II completely transformed to R-I after 15min at the same storage conditions, indicating that defects sustained during processing reduced the energy barrier for transformation, allowing it to occur. R-II was subjected to both cryogenic milling and impact milling at ambient temperature for various durations. Cryomilling resulted in an in situ progressive reduction of crystallinity, with complete conversion to amorphous ribavirin after 2h. Limited molecular mobility attributable to the low milling temperature (Texp=-196°C) likely inhibited recrystallization, allowing the amorphous solid to persist. In contrast, continuous impact milling at ambient temperature resulted in complete in situ conversion from R-II to R-I after 3h. The data suggested rapid conversion to R-I from highly disordered regions during extended milling, facilitated by localized heat buildup that likely exceeded Tg and/or Ttr.

Experimental Determination and Theoretical Calculation of the Eutectic Composition of Cefuroxime Axetil Diastereomers.

Cefuroxime axetil (CFA), an ester prodrug of cefuroxime exists as a pair of diastereoemers, namely isomer A and isomer B. To enable phase diagram construction, crystallization of the diastereomers of CFA from the commercially available amorphous drug substance was carried out. Isomer A was separated with a purity approaching 100% whereas the maximum purity of isomer B was 85% as confirmed by solution state proton NMR spectroscopy. The crystalline forms of isomer A and isomer B were confirmed as forms AI and BI, respectively, based on differential scanning calorimetry (DSC) analysis and powder X-ray diffraction. DSC analysis was used to observe the melting behavior of different diastereomer mixture compositions. The binary solid-liquid phase diagram for mixture compositions ranging from 0 to 85% w/w isomer B indicated the formation of a eutectic mixture having a melting temperature of 124.7 ± 0.4°C and a composition of 75% w/w (+/-5% wt.) isomer B. The eutectic composition was calculated using an index based on the van't Hoff equation for melting point depression and was found to be 75% isomer B and 25% isomer A. As CFA is present in commercial preparations as a mixture of diastereomers, the formation of a eutectic mixture between the diastereomers may impact the solubility and stability of the commercial product. Eutectic formation can be explained on the basis of the chemical similarity of diastereomers that favor miscibility in the liquid state.

Improved Flux of Levodopa via Direct Deposition of Solid Microparticles on Nasal Tissue.

Epithelial flux and permeability across bovine olfactory tissue were compared when levodopa (L-DOPA) was loaded in different physical states. Aqueous solution of L-DOPA was prepared in Krebs-Ringer buffer (KRB), at a concentration (0.75 mg/mL) verified to be less than the saturation solubility at both 25 and 37°C. Sodium metabisulfite was added to solution to minimize L-DOPA oxidation; chemical stability of aqueous L-DOPA was evaluated using HPLC-UV. Solid-state characterization of unprocessed, dry, crystalline L-DOPA powder was performed using TGA, DSC, PXRD, and optical microscopy to ensure that preparation of L-DOPA microparticles used for diffusion experiments did not elicit a phase change. Measurements of in vitro flux were made for all preparations, using freshly excised bovine olfactory mucosal membrane. Samples obtained from transport studies were analyzed by HPLC-UV. Tissue viability was measured before and after experiments using transdermal epithelial electrical resistance (TEER). The average steady-state flux (J ss ) of L-DOPA from solid microparticles directly deposited on nasal epithelial tissue was 6.08 ± 0.69 µg/cm2/min, approximately three times greater than the J ss measured for L-DOPA from solution (2.13 ± 0.97 µg/cm2/min). The average apparent permeability coefficient (P app ) of L-DOPA was calculated to be 4.73 × 10-5 cm/s. These findings suggest that nasal delivery of L-DOPA by administration of solid microparticles not only benefits from improved chemical and microbiological stability by avoiding the use of aqueous formulation vehicle but also does not compromise cumulative mass transport across the olfactory membrane.