Predicting the Solubility Advantage of Amorphous Drugs: Effect of pH.

The solubility enhancement generated by an amorphous phase over its crystalline counterpart is unaffected by the pH of the solution (at fixed ionic strength and temperature), even for a drug containing ionizable moieties, provided that both the ionized and neutral species generated through dissolution of the solids remain dissolved.

Modeling Recrystallization Kinetics Following the Dissolution of Amorphous Drugs.

Amorphous phases are frequently employed to overcome the solubility limitation that is nowadays commonplace in developmental small-molecule drugs intended for oral administration. However, since the solubility enhancement has finite longevity (it is a "kinetic solubility" effect), characterizing its duration (i.e., the so-called "parachute" effect) can be important for optimizing a formulation with regard to its in vivo exposure. Two semiempirical models, based on dispersive kinetics theory, are evaluated for their ability to precisely describe experimental transients depicting a loss in supersaturation (initially generated by the dissolution of the amorphous phase) over time, as the solubilized drug recrystallizes. It is found that in cases where the drug solubility significantly exceeds that of the crystal at longer times, the mechanism has substantial "denucleation" (dissolution) character. On the other hand, "nucleation and growth" (recrystallization) kinetics best describe systems in which the recrystallization goes to completion within the experimental time frame. Kinetic solubility profiles taken from the recent literature are modeled for the following drugs: glibenclamide, indomethacin, loratadine, and terfenadine. In the last case, a combination of three different kinetic models, two classical ones plus the dispersive model, are used together in describing the entire dissolution-recrystallization transient of the drug, obtaining a fit of R2 = 0.993. By precisely characterizing the duration of the "parachute" in vitro (e.g., under biorelevant conditions), the proposed models can be useful in predicting trends and thereby guiding formulation development and optimization.

Predicting the solubility enhancement of amorphous drugs and related phenomena using basic thermodynamic principles and semi-empirical kinetic models.

The accurate prediction of the solubility enhancement offered by neat amorphous drugs and amorphous solid dispersions, over their crystalline (API) counterparts, has been discussed in several landmark works dating back at least two decades. Against this backdrop, an assessment of the current state-of-the-art for rigorously, yet simply (circumventing computational methods), determining the amorphous:crystalline solubility ratio based on thermo-analytical quantities is presented herein. Included in this work is a brief survey of the literature together with a discussion of the advantages and shortcomings of some of the most popular approaches, to-date. While the focus is on neat amorphous drugs, both before and after moisture sorption, the methodology presented is readily extended to more complex (e.g. ternary) systems that form a single, homogeneous phase. Six key questions are addressed in the context of how to most accurately determine the amorphous:crystalline solubility ratio: (1) How is the lattice energy of the crystalline phase assessed? (2) What is the role of heat capacity? (3) How does the pKa impact the solubility ratio prediction (for ionizable drugs)? (4) How does one incorporate the effects of moisture sorption on the amorphous phase? (5) How might one characterize (predict) the rate of drug recrystallization under various conditions (since the duration of the solubility enhancement is a kinetic phenomenon)? (6) What is the best approach for linking the (loss in) solubility enhancement to the Tg-lowering of the amorphous drug (by water) and vice-versa? In addressing these questions, this work aims to put forth a standardized methodology for determining the amorphous solubility enhancement with improved accuracy.

Predicted amorphous solubility and dissolution rate advantages following moisture sorption: Case studies of indomethacin and felodipine.

Water is often readily absorbed by amorphous compounds, lowering their glass transition temperature (Tg) and facilitating their recrystallization (via nucleation-and-growth). At the same time, the increase in moisture content translates to a decrease in both the thermodynamic solubility and intrinsic dissolution rate, as compared to the corresponding dry (pure) amorphous phase, e.g. see [Murdande SB, Pikal MJ, Shanker RM, Bogner RH. 2010. Solubility advantage of amorphous pharmaceuticals: I. A thermodynamic analysis. J Pharm Sci 99:1254-1264.]. In the case of pure indomethacin and felodipine, the solubility advantage of each amorphous phase over its crystalline counterpart were previously determined to be 7.6 and 4.7, respectively, using a new methodology together with basic calorimetric data taken from the literature. Herein, we demonstrate that, theoretically, following the uptake of just ∼0.5% w/w water, the solubility ratios decrease to 6.9 and 4.5, in the same order. Moreover, as the predicted intrinsic dissolution rate (based on the Noyes-Whitney equation) is directly proportional to the solubility advantage of a given amorphous-crystalline pair, it decreases proportionately upon moisture uptake. Applying the methodology presented herein, one can directly predict the extent of Tg-lowering observed at any moisture content, for a given amorphous phase. Knowing that value, it is possible to estimate the relative decrease in the solubility and/or intrinsic dissolution rate of the plasticized phase compared to the pure glass, and vice-versa.

The amorphous state: first-principles derivation of the Gordon-Taylor equation for direct prediction of the glass transition temperature of mixtures; estimation of the crossover temperature of fragile glass formers; physical basis of the "Rule of 2/3".

Predicting the glass transition temperature (Tg) of mixtures has applications that span across industries and scientific disciplines. By plotting experimentally determined Tg values as a function of the glass composition, one can usually apply the Gordon-Taylor (G-T) equation to determine the slope, k, which subsequently can be used in Tg predictions. Traditionally viewed as a phenomenological/empirical model, this work proposes a physical basis for the G-T equation. The proposed equations allow for the calculation of k directly and, hence, they determine/predict the Tg values of mixtures algebraically. Two derivations for k are provided, one for strong glass-formers and the other for fragile mixtures, with the modeled trehalose-water and naproxen-indomethacin systems serving as examples of each. Separately, a new equation is described for the first time that allows for the direct determination of the crossover temperature, Tx, for fragile glass-formers. Lastly, the so-called "Rule of 2/3", which is commonly used to estimate the Tg of a pure amorphous phase based solely on the fusion/melting temperature, Tf, of the corresponding crystalline phase, is shown to be underpinned by the heat capacity ratio of the two phases referenced to a common temperature, as evidenced by the calculations put forth for indomethacin and felodipine.

Practical Estimation of Amorphous Solubility Enhancement Using Thermoanalytical Data: Determination of the Amorphous/Crystalline Solubility Ratio for Pure Indomethacin and Felodipine.

Use of amorphous phases can mitigate the low in vivo exposures of poorly soluble, crystalline active pharmaceutical ingredients. However, it remains challenging to accurately predict the solubility enhancement offered even by a pure amorphous phase relative to the crystalline form. In this work, a methodology is presented that allows estimation of the amorphous:crystalline solubility ratio, α, using only measured thermodynamic quantities for each of the pure phases. With this approach, α values of 7.6 and 4.7 were calculated for indomethacin and felodipine, respectively, correlating more closely than previous predictions with the experimentally measured values of 4.9 and 4.7 reported in the literature. There are 3 key benefits to this approach. First, it uses simple mathematical functions to more precisely relate the temperature variations in the heat capacity (Cp) to allow a more accurate estimation of the configurational energy difference between the 2 phases, whereas traditional models typically assume that Cp of both phases are constant(s). Second, the Hoffman equation is leveraged in translating the free energy of crystal lattice formation to the actual temperature of interest (selected to be 25°C/298K in this work), again, for better accuracy. Finally, as only 2 modulated differential scanning calorimetry scans are required (one for each phase), it is attractive from an experimental simplicity standpoint.

A study of variable hydration states in topotecan hydrochloride.

Topotecan hydrochloride, a pharmaceutical compound developed as a treatment for cancer, exhibits variable hydration states in a crystalline solid form chosen for manufacturing. This variability requires additional controls for successful development, and presents a characterization and detection challenge for analytical methods. In this study, overall water content was determined by Karl Fischer titration and thermogravimetric analysis (TGA) on topotecan HCl equilibrated at different relative humidity levels. These results, when combined with information obtained from dynamic water vapor sorption and differential scanning calorimetry (DSC), indicate that this form of topotecan HCl contains 3 mol of water integral to the crystalline structure and up to two additional moles of water depending on the relative humidity. Powder X-ray diffraction experiments did not detect significant differences in topotecan HCl samples equilibrated at trihydrate and pentahydrate states, and showed that the crystal lattice dimensions are not affected unless the form is dried below the trihydrate state. This behavior is typical of crystal structures with channels that can accommodate additional loosely bound water. To study the role of the loosely bound water in the crystal structure in more detail, solid-state (13)C and (15)N nuclear magnetic resonance (NMR) were used to examine the differences between the hydration states. Both the trihydrate and pentahydrate states yielded similar solid-state NMR spectra, consistent with the lack of change in the crystal lattice. However, minor but readily detectable differences in the (13)C spectra are observed with changes in water content. Interpretation of this data suggests that the loosely bound channel water is hydrogen-bonding to specific portions of the topotecan parent molecule. Topotecan HCl trihydrate was hydrated with D(2)O vapor to confirm the nature and location of the channel water using (13)C and (2)H solid-state NMR. Despite the detectable association of the channel water with hydrogen bonding sites on the topotecan molecule, (2)H quadrupolar echo experiments indicate that the channel water is highly mobile at room temperature and at -60 degrees C.

Structural analysis of polymorphism and solvation in tranilast.

Five polymorphic forms of tranilast were characterized by thermal, diffractometric, and spectroscopic techniques. The crystal structures of the most stable anhydrous form (Form I), a chloroform solvate, and a dichloromethane solvate were determined from single-crystal X-ray analysis. Two additional anhydrous forms of tranilast (Forms II and III) were also studied, but were not amenable to SCXRD. All five forms were also analyzed using solid-state nuclear magnetic resonance, Fourier transform infrared, and Fourier transform-Raman spectroscopy, and thermal methods. From the trends observed in the crystal structures and the spectral data, some conclusions can be made about hydrogen bonding, molecular conformation, and crystal packing differences in the polymorphs and solvates. Form II was found to be a spectroscopically distinctive polymorph that is probably missing an important intramolecular hydrogen bond coupled with a conformational change. In contrast, Form III was found to be more similar to the crystallographically characterized forms, and is more likely a packing and hydrogen-bonding polymorph with a weakened intermolecular hydrogen-bonding interaction relative to the other forms. From a pharmaceutical development perspective, it is shown that although the anhydrous forms of tranilast have similar thermal properties, they can be reliably distinguished by spectroscopic methods.