Characterization of humidity-dependent changes in crystal properties of a new HMG-CoA reductase inhibitor in support of its dosage form development

Morris, Kenneth R.; Newman, Ann; Bugay, David E.; Ranadive, Sunanda A.; Singh, Ambarish K.; Szyper, Mira; Varia, Sailesh A.; Brittain, Harry G.; Serajuddin, Abu T.M.

doi:10.1016/0378-5173(94)90128-7

Cited by 30 publications

(13 citation statements)

References 18 publications

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“…Among these different forms of theophylline and their mixtures, different release rates and solubilities have been reported 3,4,7–9. Traditionally, pseudopolymorphic changes have been studied using infrared (IR) spectroscopy, thermal methods, optical and electron microscopy, nuclear magnetic resonance (NMR) spectroscopy, and X‐ray diffraction 10–13. These methods are reliable, but relatively slow and limited to off‐line and at‐line applications.…”

Section: Introductionmentioning

confidence: 99%

Novel Identification of Pseudopolymorphic Changes of Theophylline During Wet Granulation Using Near Infrared Spectroscopy

Räsänen

Rantanen

Jørgensen

et al. 2001

Journal of Pharmaceutical Sciences

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Section: Introductionmentioning

confidence: 99%

Novel Identification of Pseudopolymorphic Changes of Theophylline During Wet Granulation Using Near Infrared Spectroscopy

Räsänen

Rantanen

Jørgensen

et al. 2001

Journal of Pharmaceutical Sciences

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“…2–9 However, amorphous APIs are typically metastable, with the potential to crystallize over time scales that vary considerably from compound to compound, with external conditions such as temperature and relative humidity, and with the matrix or formulation in which the API resides. 10–13 Several strategies have been utilized to stabilize amorphous formulations, including the use of polymeric crystallization inhibitors to form amorphous solid dispersions (ASD), as opposed to amorphous API powders. 5,6,14,15 Nevertheless, major challenges emerge in assessing the long-term stability of amorphous formulations, particularly for low API loadings and early stages of crystal formation.…”

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confidence: 99%

Parts per Million Powder X-ray Diffraction

et al. 2015

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Here we demonstrate the use of second harmonic generation (SHG) microscopy-guided synchrotron powder X-ray diffraction (PXRD) for the detection of trace crystalline active pharmaceutical ingredients in a common polymer blend. The combined instrument is capable of detecting 100 ppm crystalline ritonavir in an amorphous hydroxypropyl methylcellulose matrix with a high signal-to-noise ratio (>5000). The high spatial resolution afforded by SHG microscopy allows for the use of a minibeam collimator to reduce the total volume of material probed by synchrotron PXRD. The reduction in probed volume results in reduced background from amorphous material. The ability to detect low crystalline loading has the potential to improve measurements in the formulation pipeline for pharmaceutical solid dispersions, for which even trace quantities of crystalline active ingredients can negatively impact the stability and bioavailability of the final drug product.

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“…The techniques were described earlier. 3 To maximize the detection of possible physical changes in drug substances during analyses by these techniques, drug concentrations in the mixtures were usually kept at 25% or higher. It was also advantageous to limit the excipient to one that would have the least interference with the analysis of drug substances.…”

Section: Methodsmentioning

confidence: 99%

“…We have studied such changes by recording powder X-ray diffraction patterns of a drug-excipient blend initially and after mixing with water and drying. 3 Salt SelectionsThe model was also applied to determine the relative stability of different salt forms of a compound. 26 Inorganic and organic acids and bases used to prepare salts may interact with drug molecules.…”

Section: Figure 8samountsmentioning

confidence: 99%

Selection of solid dosage form composition through drug–excipient compatibility testing

Serajuddin

Thakur

Ghoshal

et al. 1999

Journal of Pharmaceutical Sciences

174

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A drug-excipient compatibility screening model was developed by which potential stability problems due to interactions of drug substances with excipients in solid dosage forms can be predicted. The model involved storing drug-excipient blends with 20% added water in closed glass vials at 50 degrees C and analyzing them after 1 and 3 weeks for chemical and physical stability. The total weight of drug-excipient blend in a vial was usually kept at about 200 mg. The amount of drug substance in a blend was determined on the basis of the expected drug-to-excipient ratio in the final formulation. Potential roles of several key factors, such as the chemical nature of the excipient, drug-to-excipient ratio, moisture, microenvironmental pH of the drug-excipient mixture, temperature, and light, on dosage form stability could be identified by using the model. Certain physical changes, such as polymorphic conversion or change from crystalline to amorphous form, that could occur in drug-excipient mixtures were also studied. Selection of dosage form composition by using this model at the outset of a drug development program would lead to reduction of "surprise" problems during long-term stability testing of drug products.

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Characterization of humidity-dependent changes in crystal properties of a new HMG-CoA reductase inhibitor in support of its dosage form development

Cited by 30 publications

References 18 publications

Novel Identification of Pseudopolymorphic Changes of Theophylline During Wet Granulation Using Near Infrared Spectroscopy

Novel Identification of Pseudopolymorphic Changes of Theophylline During Wet Granulation Using Near Infrared Spectroscopy

Parts per Million Powder X-ray Diffraction

Selection of solid dosage form composition through drug–excipient compatibility testing

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