How Does Residual Water Affect the Solid-state Degradation of Drugs in the Amorphous State?

Shalaev, Evgenyi; Zografi, George

doi:10.1021/js960257o

Cited by 165 publications

(99 citation statements)

References 21 publications

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“…This is to be expected as water has a direct role in the transesterification reaction, but reduction in degradation rate can also be due to a loss of molecular mobility induced by the solid state. [26][27][28] However, if that is well established for pharmaceuticals, there is no direct evidence for nucleic acids.…”

Section: Discussionmentioning

confidence: 99%

An efficient method for long-term room temperature storage of RNA

Fabre

Colotte²,

Luis³

et al. 2013

Eur J Hum Genet

111

110

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RNA is a tool used in many fields, from molecular and cellular biology to medicine and nanotechnology. For most of these uses, the integrity of RNA is required and must be maintained during storage. Even though freezing is currently the storage method of choice, the increasing number of samples to be stored and the costly use of a cold chain have highlighted the need for room temperature preservation methods. Here, we report a new room temperature technology that consists in drying RNA samples in the presence of a stabilizer in stainless steel minicapsules. These air-and water-tight capsules isolate RNA from the atmosphere and maintain an anhydrous and anoxic environment. Through the evaluation of RNA integrity over time at room temperature or 90 1C, we identified atmospheric humidity as a major deleterious factor. The degradation rate dependence in temperature fitted an Arrhenius model, with an activation energy of 28.5 kcal/mol and an extrapolated room temperature degradation rate of 3.2 10 À13 /nt/s (95% confidence interval: 2.3-4.2/nt/s). In these conditions, it is expected that an RNA molecule will be subjected to 0.7-1.3 cut every 1000 nucleotides per century. In addition, we showed that stored RNA is compatible for further analyses, such as reverse transcription-quantitative PCR. No significant change in the C q values was observed over a simulated period of several decades. At last, our data are consistent with a sequence-independent degradation rate of RNA in the solid state.

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Section: Discussionmentioning

confidence: 99%

An efficient method for long-term room temperature storage of RNA

Fabre

Colotte²,

Luis³

et al. 2013

Eur J Hum Genet

111

110

View full text Add to dashboard Cite

show abstract

“…1), and this sample had the lowest T g and T m values (Table II). Residual moisture has a plasticizing effect on proteins and acts by reducing the T g of the protein sample and enhancing molecular mobility in the solid matrix (11). A second prominent endothermic peak was observed for the five samples, which could be attributed to melting (T m ).…”

Section: Thermal Analysesmentioning

confidence: 96%

“…For example, the presence of residual moisture in pharmaceutical protein or peptide drugs could result in water-protein interactions, which could affect the potency of the drug or cause excessive increase in the level of decomposition (10). Residual moisture can act as a reactant or product in the degradation pathways of the peptide, serve as a medium in which degradation occurs, or act as a plasticizer by reducing the glass transition temperature (T g ) and enhancing the mobility of reactants in the solid matrix (11). Residual moisture refers to the low level of surface water, ranging from less than 1 to 5%, remaining in a lyophilized biological product after the bulk of the aqueous solvent has been removed (12).…”

Section: Thermal Analysesmentioning

confidence: 99%

Physicochemical Characterization of Complex Drug Substances: Evaluation of Structural Similarities and Differences of Protamine Sulfate from Various Sources

Awotwe-Otoo

Agarabi

Keire³

et al. 2012

AAPS J

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Abstract. The purpose of this study was to characterize and evaluate differences of protamine sulfate, a highly basic peptide drug, obtained from five different sources, using orthogonal thermal and spectroscopic analytical methods. Thermogravimetric analysis and modulated differential scanning calorimetry showed that all five protamine sulfate samples had different moisture contents and glass transition and melting temperatures when temperature was modulated from 25 to 270°C. Protamine sulfate from source III had the highest residual moisture content (4.7±0.2%) at 105°C, resulting in the lowest glass transition (109.7°C) and melting (184.2°C) temperatures compared with the other four sources. By Fourier-transform infrared (FTIR) spectroscopy, the five sources of protamine sulfate had indistinguishable spectra, and the spectra were consistent with a predominantly random coil conformation in solution and a minor population in a β-sheet conformation (~12%). Circular dichroism spectropolarimetry confirmed the FTIR results with prominent minima at 206 nm observed for all five sources. Finally, proton ( 1 H) nuclear magnetic resonance spectroscopy showed that all five protamine sulfate sources had identical spectra with backbone amide chemical shifts between 8.20 and 8.80 ppm, consistent with proteins with predominantly random coil conformation. In conclusion, thermal analyses showed differences in the thermal behavior of the five sources of protamine sulfate, while spectroscopic analyses showed the samples had a predominantly random coil conformation with a small amount of β-sheet present.

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“…The humidity during storage is another important factor affecting the hygroscopic nature of hydrophilic polymers. The plasticizing effect of absorbed moisture can reduce the T g of amorphous substance and lead to further instability (41,42). Thus, appropriate storage conditions (aging) are necessary to be selected during accelerated stability studies.…”

Section: Thermal Analysismentioning

confidence: 99%

Physicochemical Investigations and Stability Studies of Amorphous Gliclazide

Jondhale¹,

Bhise²,

Pore³

2012

AAPS PharmSciTech

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Abstract. Gliclazide (GLI), a poorly water-soluble antidiabetic, was transformed into a glassy state by melt quench technique in order to improve its physicochemical properties. Chemical stability of GLI during formation of glass was assessed by monitoring thin-layer chromatography, and an existence of amorphous form was confirmed by differential scanning calorimetry and X-ray powder diffractometry. The glass transition occurred at 67.5°C. The amorphous material thus generated was examined for its in vitro dissolution performance in phosphate buffer (pH 6.8). Surprisingly, amorphous GLI did not perform well and was unable to improve the dissolution characteristics compared to pure drug over entire period of dissolution studies. These unexpected results might be due to the formation of a cohesive supercooled liquid state and structural relaxation of amorphous form toward the supercooled liquid region which indicated functional inability of amorphous GLI from stability point of view. Hence, stabilization of amorphous GLI was attempted by elevation of T g via formation of solid dispersion systems involving comprehensive antiplasticizing as well as surface adsorption mechanisms. The binary and ternary amorphous dispersions prepared with polyvinylpyrrolidone K30 (as antiplasticizer for elevation of T g ) and Aerosil 200® and/or Sylysia® 350 (as adsorbent) in the ratio of 1:1:1 (w/w) using kneading and spraydrying techniques demonstrated significant enhancement in rate and extent of dissolution of drug initially. During accelerated stability studies, ternary systems showed no significant reduction in drug dissolution performance over a period of 3 months indicating excellent stabilization of amorphous GLI.

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How Does Residual Water Affect the Solid-state Degradation of Drugs in the Amorphous State?

Cited by 165 publications

References 21 publications

An efficient method for long-term room temperature storage of RNA

An efficient method for long-term room temperature storage of RNA

Physicochemical Characterization of Complex Drug Substances: Evaluation of Structural Similarities and Differences of Protamine Sulfate from Various Sources

Physicochemical Investigations and Stability Studies of Amorphous Gliclazide

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