A gel is presented
which represents a new category of pharmaceutical
active ingredient in addition to the conventional crystalline and
amorphous forms. The crystal structure of atorvastatin calcium ethylene
glycol solvate suggests atorvastatin calcium to be a low-molecular
weight organogelator that forms organogels with a wide variety of
alkyl alcohols. Metal ion driven ionic interactions based on the amphiphilic
nature of atorvastatin calcium leads to a lamellar type packing structure.
Like ethylene glycol in its solvated form, alkyl alcohols, ranging
from ethanol to octanol, can interact with the metal ions, and/or
occupy the void spaces within that lamellar structure, thereby forming
organogels featuring highly varying solubilities and unusual phase
transition behaviors. An in situ dissolution study identified changes
in the amounts/ratios of solvents in the atorvastatin calcium organogels
without any significant structural changes, indicating that simultaneous
solvent exchange is the mechanism of phase transition during dissolution.
The presented low molecular gelator system may also be observed with
the other statins that share common structural features with atorvastatin
calcium as well as with other pharmaceutical materials. Thus, we propose
a new form of active pharmaceutical ingredient, a gel. Since gels
show important pharmaceutical properties quite distinct from those
of crystalline or amorphous forms, they deserve special attention.
Roflumilast is currently administered orally to control acute exacerbations in chronic obstructive pulmonary disease (COPD). However, side effects such as gastrointestinal disturbance and weight loss have limited its application. This work aimed to develop an inhalable roflumilast formulation to reduce the dose and potentially circumvent the associated toxicity. Roflumilast was cospray-dried with trehalose and L-leucine with varied feed concentrations and spray-gas flow rates to produce the desired dry powder. A Next-Generation Impactor (NGI) was used to assess the aerosolization efficiency. In addition, different devices (Aerolizer, Rotahaler, and Handihaler) and flow rates were used to investigate their effects on the aerosolization efficiency. A cytotoxicity assay was also performed. The powders produced under optimized conditions were partially amorphous and had low moisture content. The powders showed good dispersibility, as evident by the high emitted dose (>88%) and fine particle fraction (>52%). At all flow rates (≥30 L/min), the Aerolizer offered the best aerosolization. The formulation exhibited stable aerosolization after storage at 25 °C / 15% Relative Humidity (RH) for one month. Moreover, the formulation was non-toxic to alveolar basal epithelial cells. A potential inhalable roflumilast formulation including L-leucine and trehalose has been developed for the treatment of COPD. This study also suggests that the choice of device is crucial to achieve the desired aerosol performance.
Three crystal structures of donepezil salts formed with sulfonic acids were obtained. Interestingly, donepezil-besylate and donepezil-tosylate share similar crystal molecular conformations and crystal packing. On the basis of PXRD patterns, donepezil-mesylate and donepezil-esylate are likely to share similar crystal structures. The sulfonyl hydroxides of all three sulfonic acids form an intermolecular hydrogen bond with the piperidyl amine of donepezil. Solid state characterization showed that the T g 's of all four amorphous donepezil salts are similar to each other and increase significantly compared to T g of donepezil. Stability analysis found that the amorphous salts of donepezil formed with mesylate and esylate led to significantly improved physical stability under accelerated stability conditions, but the other donepezil-sulfonic acid salts did not. Solubility data showed that mesylate/esylate salts of donepezil significantly increase the solubility of donepezil that is not shown by other salt forms. Solubility analysis indicated that the solubility of donepezil-mesylate and donepezil-esylate is extremely high compared to that of donepezil-besylate and donepezil-tosylate. We concluded that the extremely high solubility is responsible for delaying the rate of nucleation and thus improving the physical stability of amorphous donepezil. This study highlights that the aqueous solubility of amorphous material is an important factor when considering the physical stability of amorphous material under high relative humidity.
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