On the solubility advantage of a pharmaceutical’s glassy state over the crystal state, and of its crystal polymorphs

Johari, G. P.; Shanker, Ravi

doi:10.1016/j.tca.2014.10.012

Cited by 13 publications

(14 citation statements)

References 59 publications

(173 reference statements)

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“…It should be noted that the calculation by eq 1 predicts the solubility advantage of a f reshly melt-quenched amorphous solid equilibrated with water in an inf initesimal amount of time, during which no structural relaxation occurs. In reality, amorphous solid absorbs water and relaxes toward a lower energy state during the solubility measurement, 32 which might explain the overall greater predicted amorphous solubility advantage than experimentally measured. Overall, the data presented on the model compounds quantitatively validate the calculation method for assessing amorphous solubility advantage.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Evaluation of Accuracy of Amorphous Solubility Advantage Calculation by Comparison with Experimental Solubility Measurement in Buffer and Biorelevant Media

Zhang

Haser²,

Hou

et al. 2018

Mol. Pharmaceutics

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The accuracy of amorphous solubility advantage calculation was evaluated by experimental solubility measurement. Ten structurally diverse compounds were studied to test the generlity of the theoretical calculation. Three reported methods of calculating Gibbs free energy difference between amorphous and crystalline solids were evaluated. Experimental solubility advantage was measured by direct dissolution of amorphous solid in buffer. When necessary, hydroxypropyl methylcellulose acetate succinate (HPMCAS) was predissolved in buffer to inhibit desupersaturation. By direct dissolution, the effect of different preparation methods on amorphous solubility was also studied. Finally, solubility measurement was performed in fasted state simulated intestinal fluid (FaSSIF) to assess the effect of bile salt on the concentration-based amorphous solubility advantage. The results showed that the assumption of constant heat capacity differences between crystal and supercooled liquid or amorphous solid is sufficient for accurate theoretical calculation, which is attributed to the fact that the heat capacity of crystal is nearly parallel to that of supercooled liquid or amorphous solid. Different preparation methods do not have significant impact on amorphous solubility advantage. Experimental measurement agrees with the theoretical calculation within a factor of 0.7 to 1.8. The concentration-based amorphous solubility advantage in FaSSIF agrees well with theoretical calculation. This work demonstrates that theoretical calculation of amorphous solubility advantage is robust and can be applied in early drug development for assessing the utility of the amorphous phase.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Evaluation of Accuracy of Amorphous Solubility Advantage Calculation by Comparison with Experimental Solubility Measurement in Buffer and Biorelevant Media

Zhang

Haser²,

Hou

et al. 2018

Mol. Pharmaceutics

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“…Therefore, increasing the bioavailability of medicines has become a major challenge for the pharmaceutical industry, and amorphization appears as a good way to improve the solubility and dissolution rate of the drugs. [1][2][3][4] Indeed, the glassy state exhibits a disordered molecular arrangement that gives rise to appreciably lower packing energy compared to the crystalline form; however, it is not a state of equilibrium whereby it has instability which may, in certain cases, negate the advantages of its greater solubility: the glass ages, especially at temperatures not much lower than T g , and can recrystallize during processing or storage. The widespread belief in a correlation between molecular mobility and the instability of the amorphous state has led to numerous studies aiming to ground this idea.…”

Section: Introductionmentioning

confidence: 99%

Thermal behavior and molecular mobility in the glassy state of three anti-hypertensive pharmaceutical ingredients

Ramos

2017

RSC Adv.

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“…Solubility [1][2][3] and physical stability [4][5][6][7][8] are two essential properties of a drug. A good solubility is required to get a good bioavailability of the drug and a good physical stability is required to get a reasonable shelf life time.…”

Section: Introductionmentioning

confidence: 99%

“…A good solubility is required to get a good bioavailability of the drug and a good physical stability is required to get a reasonable shelf life time. Of course, the most stable physical form of a drug is the crystalline form because it has the lowest free enthalpy 1 . However, the crystalline form is also generally the less soluble.…”

Section: Introductionmentioning

confidence: 99%

Interest of molecular/crystalline dispersions for the determination of solubility curves of drugs into polymers

Latreche

willart

Guérain

et al. 2019

International Journal of Pharmaceutics

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We present here a method to increase the dissolution rate of drugs into polymers in order to make easier and faster the determination of the solubility curves of these mixtures. The idea is to prepare molecular/crystalline dispersions (MCD) where the drug is dispersed into the polymer, partly at the molecular level and partly in the form of small crystallites. We show that this particular microstructure greatly increases the dissolution rate of crystallites since: (1) The molecular dispersion has a plasticizing effect which greatly increases the molecular mobility in the amorphous matrix. (2) The fine crystallite dispersion in the matrix strongly reduces the distances over which the drug molecules have to diffuse to invade homogeneously the polymer by dissolution. MCD are here obtained by combining solid-state co-amorphization by high energy mechanical milling and then recrystallization by annealing under a plasticizing atmosphere. We have used MCD to determine the solubility lines of the two polymorphic forms (I and II) of sulindac into PVP. The investigations have been performed mainly by DSC and powder x-ray diffraction.

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On the solubility advantage of a pharmaceutical’s glassy state over the crystal state, and of its crystal polymorphs

Cited by 13 publications

References 59 publications

Evaluation of Accuracy of Amorphous Solubility Advantage Calculation by Comparison with Experimental Solubility Measurement in Buffer and Biorelevant Media

Evaluation of Accuracy of Amorphous Solubility Advantage Calculation by Comparison with Experimental Solubility Measurement in Buffer and Biorelevant Media

Thermal behavior and molecular mobility in the glassy state of three anti-hypertensive pharmaceutical ingredients

Interest of molecular/crystalline dispersions for the determination of solubility curves of drugs into polymers

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