The molecular basis of moisture effects on the physical and chemical stability of drugs in the solid state

Ahlneck, Claes; Zografi, George

doi:10.1016/0378-5173(90)90221-o

Cited by 483 publications

(285 citation statements)

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“…The 2 absorption of water within solid dispersions is generally deleterious, destabilizing their physical 3 structure by depressing the T g and inducing changes within the crystalline structure. As a result, 4 minimal moisture uptake is optimal for the dispersed active ingredient to remain immobilized for 5 as long as possible (Ahlneck and Zografi, 1990;Hancock and Zografi, 1994). The low water 6 sorption capacity of L-leucine particles is due to the high crystalline content Both lactose and 7 trehalose are considered to be highly hygroscopic materials and hence, it was not unexpected that 8 the spray dried particles from these ingredients similarly showed high moisture uptake in the 9 experiments.…”

Section: Moisture Uptake 12mentioning

confidence: 99%

Evaluation of excipients for enhanced thermal stabilization of a human type 5 adenoviral vector through spray drying

Leclair

Cranston

Xing

et al. 2016

International Journal of Pharmaceutics

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4We have produced a thermally stable recombinant human type 5 adenoviral vector 5 (AdHu5) through spray drying with three excipient formulations (L-leucine, lactose/trehalose 6 and mannitol/dextran). Spray drying leads to immobilization of the viral vector which is believed 7 to prevent viral protein unfolding, aggregation and inactivation. The spray dried powders were 8 characterized by scanning electron microscopy, differential scanning calorimetry, Karl Fischer 9 titrations, and X-ray diffraction to identify the effects of temperature and atmospheric moisture 10 on the immobilizing matrix. Thermal stability of the viral vector was confirmed in vitro by 11 infection of A549 lung epithelial cells. Mannitol/dextran powders showed the greatest 12 improvement in thermal stability with almost no viral activity loss after storage at 20°C for 90 13 days (0.7 ± 0.3 log TCID 50 ) which is a significant improvement over the current -80 o C storage 14 protocol. Furthermore, viral activity was retained over short term exposure (72 hours) to 15 temperatures as high as 55°C. Conversely, all powders exhibited activity loss when subjected to 16 moisture due to amplified molecular motion of the matrix. Overall, a straightforward method 17 ideal for the production of thermally stable vaccines has been demonstrated through spray drying 18AdHu5 with a blend of mannitol and dextran and storing the powder under low humidity 19 conditions. 20 21

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Section: Moisture Uptake 12mentioning

confidence: 99%

Evaluation of excipients for enhanced thermal stabilization of a human type 5 adenoviral vector through spray drying

Leclair

Cranston

Xing

et al. 2016

International Journal of Pharmaceutics

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“…Water acts as a plasticizer for amorphous systems, causing an increase in the free volume and a reduction in the T g of the system. Enhanced molecular mobility, caused by plasticization, has been proposed to be the underlying factor in the chemical and the physical instability of the amorphous pharmaceutical solids [10]. Therefore, it becomes imperative to perform an assessment of the molecular mobility to determine the suitable storage conditions for amorphous substances and their products.…”

Section: Introductionmentioning

confidence: 99%

Molecular Mobility and Physical Stability of Amorphous Irbesartan

Chawla

2009

Sci. Pharm.

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Amorphous systems have attracted considerable attention due to their favorable properties; however, their stability issues still pose a major challenge. The purpose of the present work was to investigate the role of molecular mobility and moisture in the physical stability of a selected pharmaceutical amorphous system. Irbesartan (IBS), a relatively stable glass, was chosen as the model drug, as it exhibits a good physical stability (resistance to crystallization) at temperatures below the glass transition (T g -50 K). The amorphous system was annealed at temperatures 298 K (25 °C) and 313 K (40 °C) at 0 and 75 % RH to study the effect of temperature and moisture on its relaxation behavior. Differential scanning calorimetry (DSC) was used to characterize both the crystalline and the freshly prepared glass, and to monitor the extent of relaxation at temperatures below glass transition (Tg) as well as heat capacity changes as a function of temperature. Molecular relaxation time constant (τ) decreased drastically from 302 years to 68 hours with the increase in annealing temperature as determined by Kohlrausch-William-Watts (KWW) equation. IBS was found to be 'relatively' stable in the amorphous state and presented a challenge for temporal measurements. Hence, at low annealing temperatures, (T g -50 K or below) initial relaxation time (τ 0 ) was estimated using the calorimetric based approach. Amorphous IBS was non-hygroscopic and retained its glassy nature under the accelerated stability conditions. The extent of relaxation in the amorphous drug in the presence of moisture was also estimated.

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“…This interest has arisen as a result of the suggestion that many observed phenomena such as anomalous water sorption behavior may be interpreted in terms of a surface layer of glassy material. While constituting only a small percentage of the entire mass of the sample, this layer could nevertheless constitute a significant proportion of the surface and hence have a profound effect on product performance (1). The emphasis to date in both academia and industry regarding this issue has been to attempt to quantify the proportion of amorphous material present with techniques such as microcalorimetry and vapour sorption measurements being, particularly, widely used (2).…”

Section: Commentarymentioning

confidence: 99%

“…The existence of such a fraction has not yet been directly demonstrated for low molecular weight pharmaceuticals. Indeed, such measurements are more difficult for these materials because even when "semi-crystalline" they contain 1 The School of Pharmacy, The Queen's University of Belfast, 97…”

Section: Commentarymentioning

confidence: 99%