Physical stability hydrate

The chemical and physical stability of aqueous and nonaqueous suspensions of a number of solvatomorphs of niclosamide has been evaluated in an effort to develop pharmaceutically acceptable suspension formulations [90]. Studied in this work was the anhydrate, two polymorphic monohydrates, the 1 1, Y, A"-dimethyI I ormam ide solvatomorph, the 1 1 dimethyl sulfoxide solvatomorph, the 1 1 methanol solvato-morph, and the 2 1 tetraethylene glycol hemisolvate. All of the solvatomorphs were found to convert initially to one of the polymorphic monohydrates, and over time converted to the more stable monohydrate phase. The various solvatomorphs could be readily desolvated into isomorphic desolvates, but these were unstable and became re-hydrated or re-solvated upon exposure to the appropriate solvent. 

The hydration state of risedronate sodium was monitored continuously in a fluidized bed dryer and correlated to data on the physical stability of tablets made from the monitored material [275]. The final granulation moisture was found to affect the solid-state form, which in turn dictated the drug s physical stability over time. The process of freeze-drying mannitol was monitored continuously with in-line Raman and at-line NIR spectroscopies [276]. The thin polymer solvent coatings, such as poly(vinyl acetate) with toluene, methanol, benzene, and combinations of the solvents, were monitored as they dried to generate concentra-tion/time profiles [277]. 

D.S. Hausman, R.T. Cambron and A. Sakr, Application of on-line Raman spectroscopy for characterizing relationships between drug hydration state and tablet physical stability, Int. J. Pharm., 299, 19-33 (2005). 

While DSC may be used to study pharmaceutical hydrates, the most useful thermal method is undoubtedly TGA. Hydrates are materials whereby molecules of water are incorporated into the lattice structure of that solid at specific ratios, hence a monohydrate has one molecule of water for each molecule of drug, a dihydrate two molecules of water etc. The stoichiometry may also be fractional. Hydrates are again extremely important pharmaceutically as the physical properties differ from the anhydrous form, the former having, for example, a lower water solubility. Many drugs are marketed as hydrate forms, often due to their greater physical stability than the anhydrous form which may convert to the hydrate over a period of time if exposed to water vapor. 

Wet massing Wet granulation Polymorphic conversion hydrate formation salt to free aetd/base conversion amorphous phase formation Chemical and physical stability dissolution rate... 

As a general rule, anhydrous forms that do not convert to the hydrate below 75% RH (at equilibrium) are likely to exhibit adequate physical and chemical stability in oral solid dosage forms. Adequate manufacturing and packaging can be designed to protect most oral solid dosage forms from exposure to >75% RH. Conversely, hydrates that do not convert to the anhydrous form until the relative humidity drops below about 20% (at equilibrium) are also likely to exhibit adequate physical stability in solid dosage forms. 

If the drug is insufficiently soluble to allow delivery of the required dose as a solution (the maximum delivered dose for each nostril is 200 p,L), then a suspension formulation will be required. There are additional issues for suspension products, for example crystal growth, physical stability, resuspension, homogeneity and dose uniformity. Suspension products will also require information on density, particle size distribution, particle morphology, solvates and hydrates, polymorphs, amorphous forms, moisture and/or residual solvent content and microbial quality (sterile filtration of the bulk liquid during manufacture is not feasible). 

Recognizing that the hydration state of a hydrate depends on the water activity in the crystallization medium, Zhu and Grant investigated the influence of solution media on the physical stability of the anhydrate, trihydrate, and amorphous forms of ampicillin [38], The crystalline anhydrate was found to be kinetically stable in the sense that no change was detected by powder x-ray diffraction for at least 5 days in methanol+water solutions over the whole range of water activity = 0 for pure methanol to = 1 for pure liquid water). However, addition of trihydrate seeds to ampicillin anhydrate suspended in methanol+water solutions at >0.381 resulted in the conversion of the anhydrate to the thermodynamically stable trihydrate. The trihydrate converted to the amorphous form at < 0.338 in the absence of anhydrate seeds, but it converted to the anhydrate phase at <... 

Han J, Suryanarayanan R (1999) A method for the rapid evaluation of the physical stability of pharmaceutical hydrates. Thermochimi Acta 329 163-170. 

Theophylline has also been co-crystallized with urea [87] A-(2-ammonioethyl)carba-mate [88], chlorosalicylic acid [89], sulfathiazole, 5-fluorouracil [90], p-nitroaniline [91], succinic acid, malonic acid, maleic acid and oxalic acid [92]. There is evidence that at least one of these co-crystals, between theophylline and oxalic acid, can improve the physical stability of theophylline by protecting it from converting to the less soluble hydrate at high humidities. In this case, oxalic acid and water both hydrogen bond with theophylline at the same site. It is unclear whether or not the occupancy of the hydrogen bonding site by another molecule, in this case oxalic acid prevents the conversion to the hydrate or, if a general decrease in solubility of the oxalic acid co-crystal versus the hydrate is responsible for the protective effects. 

The surface potential can play an important role in the behavior of liposomes in vivo and in vitro (e.g.. Senior, 1987). In general, charged liposomes ai e more stable against aggregation and fusion than uncharged vesicles. However, physically stable neutral liposomes have been described (e.g.. Van Dalen et al., 1988). They are sufficiently stabilized by repulsive hydration forces, which counteract the attractive van der Waals forces. 

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