Purpose To evaluate the magnitude of the solubility advantage foramorphous pharmaceutical materials when compared to their crystallinecounterpartsMethods The thermal properties of several drugs in their amorphousand crystalline states were determined using differential scanningcalorimetry From these properties the solubility advantage for theamorphous form was predicted as a function of temperature using a simplethermodynamic analysis These predictions were compared to theresults of experimental measurements of the aqueous solubilities of theamorphous and crystalline forms of the drugs at several temperaturesResults By treating each amorphous drug as either an equilibriumsupercooled liquid or a pseudo-equilibrium glass, the solubilityadvantage compared to the most stable crystalline form was predicted to bebetween 10 and 1600 fold The measured solubility advantage wasusually considerably less than this, and for one compound studied indetail its temperature dependence was also less than predicted It wascalculated that even for partially amorphous materials the apparentsolubility enhancement (theoretical or measured) is likely to influencein-vitro and in-vivo dissolution behaviorConclusions Amorphous pharmaceuticals are markedly more solublethan their crystalline counterparts, however, their experimental solubility advantage is typically less than that predicted from simplethermodynamic considerations This appears to be the result of difficulties indetermining the solubility of amorphous materials under trueequilibrium conditions Simple thermodynamic predictions can provide a useful indication of the theoretical maximum solubility advantage foramorphous pharmaceuticals, which directly reflects the driving forcefor their initial dissolution

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What is the true solubility advantage for amorphous pharmaceuticals

Nanosizing: a formulation approach for poorly-water-soluble compounds.

High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids

Salt Selection and Optimisation Procedures for Pharmaceutical New Chemical Entities

Drug polymorphism and dosage form design: a practical perspective.

Purpose. This review describes a conceptual approach to the characterization of pharmaceutical solids. 
Methods. Four flow charts are presented: (1) polymorphs, (2) hydrates, (3) desolvated solvates, and (4) amorphous forms. 
Results. These flow charts (decision trees) are suggested as tools to develop information on pharmaceutical solids for both scientific and regulatory purposes. 
Conclusions. It is hoped that this review will lead to a more direct approach to the characterization of pharmaceutical solids and ultimately to faster approval of regulatory documents containing information on pharmaceutical solids.

Pharmaceutical Solids: A Strategic Approach to Regulatory Considerations

Solid-state pharmaceutical chemistry

4-Methyl-2-nitroacetanilide (1) crystallizes in white (1W), amber (1A), and yellow (1Y) modifications. The isomorphic molecules 4-chloro-2-nitroacetanilide (2) and 2-nitro-4-trifluoromethylacetanilide (3) were synthesized, and their effects on the crystallization of 1 were studied. The percentages of an additive incorporated into the 1W, 1A, and 1Y crystal lattices were determined by HPLC. Compound 2 is incorporated as a solid solution in 1A up to levels of 30% (w/w), whereas the incorporation efficiency of 3 is much lower at the same doping level. From these results it can be assumed that 2 causes less disruption to the host lattices than does 3. At the same doping level of an additive, 1A incorporates the additive at a greater level than 1W or 1Y. As the incorporation level of an additive increases, both the solution and solid-state transformation rate from 1A to either 1W or 1Y decreases. Structural comparison of the 1W, 1A, and 1Y crystal lattices indicates that the additives may be least disruptive t...

Stabilization of a Metastable Polymorph of 4-Methyl-2-nitroacetanilide by Isomorphic Additives

Analysis of solid-state Carbon-13 NMR spectra of polymorphs (benoxaprofen and nabilone) and pseudopolymorphs (cefazolin).

Analysis of the acid–base reaction between solid indomethacin and sodium bicarbonate using infrared spectroscopy, X-ray powder diffraction, and solid-state nuclear magnetic resonance spectroscopy

Ralph R. Pfeiffer

Papers

Pharmaceutical Solids: A Strategic Approach to Regulatory Considerations

Solid-state pharmaceutical chemistry

Stabilization of a Metastable Polymorph of 4-Methyl-2-nitroacetanilide by Isomorphic Additives

Analysis of solid-state Carbon-13 NMR spectra of polymorphs (benoxaprofen and nabilone) and pseudopolymorphs (cefazolin).

Analysis of the acid–base reaction between solid indomethacin and sodium bicarbonate using infrared spectroscopy, X-ray powder diffraction, and solid-state nuclear magnetic resonance spectroscopy