Comparison of the Ability of Various Pharmaceutical Silicates to Amorphize and Enhance Dissolution of Indomethacin Upon Co-grinding

Bahl, Deepak; Hudak, J. J.; Bogner, Robin H.

doi:10.1080/10837450802012869

Cited by 55 publications

(37 citation statements)

References 24 publications

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“…1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 26 function of particle size, a dissolution experiment under sink dissolution conditions was carried out and the best fit of Equation 19 to the measured dissolution profiles of amorphous IND particles of different sizes were obtained ( Figure 6). It is not surprising that the resulting dissolution rate constant k (summarized in Table 1) increases as the particle size decreases reflecting a faster dissolution rate due to the larger available surface area of smaller particles as confirmed by many previous studies 29,38,39 . In simulating the dissolution of amorphous drug particles under nonsink conditions of this study, the dissolution or drug input rate represented by Equation 21 or the first term on the right-hand side of 19) as a function of particle size.…”

Section: Resultssupporting

confidence: 57%

Evolution of Supersaturation of Amorphous Pharmaceuticals: Nonlinear Rate of Supersaturation Generation Regulated by Matrix Diffusion

Sun

Lee

2015

Mol. Pharmaceutics

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The importance of rate of supersaturation generation on the kinetic solubility profiles of amorphous systems has recently been shown by us; however, the previous focus was limited to constant rates of supersaturation generation. The objective of the current study is to further examine the effect of nonlinear rate profiles of supersaturation generation in amorphous systems, including (1) instantaneous or infinite rate (i.e., initial degree of supersaturation), (2) first-order rate (e.g., from dissolution of amorphous drug particles), and (3) matrix diffusion regulated rate (e.g., drug release from amorphous solid dispersions (ASDs) based on cross-linked poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogels), on the kinetic solubility profiles of a model poorly soluble drug indomethacin (IND) under nonsink dissolution conditions. The previously established mechanistic model taking into consideration both the crystal growth and ripening processes was extended to predict the evolution of supersaturation resulting from nonlinear rates of supersaturation generation. Our results confirm that excessively high initial supersaturation or a rapid supersaturation generation leads to a surge in maximum supersaturation followed by a rapid decrease in drug concentration owing to supersaturation-induced precipitation; however, an exceedingly low degree of supersaturation or a slow rate of supersaturation generation does not sufficiently raise the supersaturation level, which results in a lower but broader maximum kinetic solubility profile. Our experimental data suggest that an optimal area-under-the-curve of the kinetic solubility profiles exists at an intermediate initial supersaturation level for the amorphous systems studied here, which agrees well with the predicted trend. Our model predictions also support our experimental findings that IND ASD in cross-linked PHEMA exhibits a unique kinetic solubility profile because the resulting supersaturation level is governed by a matrix diffusion regulated mechanism opposite to that resulted from a high level of initial supersaturation or a rapid dissolution of amorphous solids. This more gradual drug release from IND-PHEMA ASD leads to a more gradual buildup of a sustained supersaturation even without the presence of any dissolved polymer to inhibit the drug precipitation, which avoids the rapid surge of supersaturation above a critical value as normally associated with high initial degrees of supersaturation or rapid dissolution of amorphous IND solids and thus avoids the onset of fast uncontrolled precipitation. This characteristic feature makes cross-linked insoluble PHEMA an attractive carrier for amorphous pharmaceuticals.

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Section: Resultssupporting

confidence: 57%

Evolution of Supersaturation of Amorphous Pharmaceuticals: Nonlinear Rate of Supersaturation Generation Regulated by Matrix Diffusion

Sun

Lee

2015

Mol. Pharmaceutics

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“…Yang et al (12) showed a slower dissolution rate of prednisone compared to its crystalline form. An improvement in the dissolution rate and bioavailability of indomethacine by interaction with silica was reported by Watanabe et al (13) Most of the previous studies on cogrinding reported a dramatic increase in the dissolution rate of drug amorphized by cogrinding technique with carrier (14,15). The product obtained from the cogrinding process can be packaged into sachets as powder form with pharmaceutically acceptable excipients.…”

Section: Introductionmentioning

confidence: 87%

Cogrinding as a Tool to Produce Sustained Release Behavior for Theophylline Particles Containing Magnesium Stearate

et al. 2009

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Abstract. The aim of the present study was to explore the cogrinding technique as a tool to slow down the drug release from capsule formulations. To this end, the physical mixtures of theophyllinemagnesium stearate were prepared and subjected to different milling times (1, 15, 30, 120 min). In order to investigate the effect of magnesium stearate concentration on drug release, various concentrations of magnesium stearate (1%, 3%, 5%, and 10%, w/w) were used. The dissolution rate of the drug from coground samples and physical mixtures were determined at pH 6.5 according to USP. The results showed that all coground formulations showed slower release rates than their physical mixture counterparts. The effect of cogrinding time on the drug release was complex. Cogrinding time had no significant effect on drug release when the amount of magnesium stearate was 1% (w/w). When the amount of magnesium stearate was increased from 1% to 3% and cogrinding time increased from 1 to 5 min, there was a significant reduction in drug release. Beyond 5-min cogrinding, the drug release increased again. For coground samples containing 5% or 10% (w/w) magnesium stearate, generally, the highest drug release was obtained at higher cogrinding time. This was due to a significant increase in surface area of particles available for dissolution as proven by scanning electron microscopy results. Fourier transform infrared and differential scanning calorimetry results ruled out any significant interaction between theophylline and magnesium stearate in solid state.

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“…In order to overcome these problems and improve the milling efficiency, a favorable technique by co-milling drug with additives has been successfully applied (Descamps et al, 2007a,b;Bahl et al, 2008;Colombo et al, 2009). Furthermore, the co-milling process can not only prepare amorphous solids, nanoparticles, inclusion complexes, and solid dispersions (Watanabe et al, 2003;Wongmekiat et al, 2007;Balani et al, 2010;Ranpise et al, 2010) but also produce sustained release behavior for drug particles (Nokhodchi et al, 2009).…”

Section: Introductionmentioning

confidence: 97%

Solid-state transformation of different gabapentin polymorphs upon milling and co-milling

Lin

Hsu²,

Ke³

2010

International Journal of Pharmaceutics

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Comparison of the Ability of Various Pharmaceutical Silicates to Amorphize and Enhance Dissolution of Indomethacin Upon Co-grinding

Cited by 55 publications

References 24 publications

Evolution of Supersaturation of Amorphous Pharmaceuticals: Nonlinear Rate of Supersaturation Generation Regulated by Matrix Diffusion

Evolution of Supersaturation of Amorphous Pharmaceuticals: Nonlinear Rate of Supersaturation Generation Regulated by Matrix Diffusion

Cogrinding as a Tool to Produce Sustained Release Behavior for Theophylline Particles Containing Magnesium Stearate

Solid-state transformation of different gabapentin polymorphs upon milling and co-milling

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