Solid stability moisture

Even in the presence of considerable moisture, solid polymer never forms above 30°C (23). Below 30°C, liquid stability decreases with increasing moisture and decreasing temperature (23). The actual formation of solid polymer has been hypothesized to involve the formation in the liquid of high molecular weight polysulfuric acids, followed by precipitation. 

The nitrogen heteroatoms in imidazole and some closely related heterocycles can stabilize a carbene center at the 2-position (97AG(E)2162). Thus, 1,3-disubstituted imidazole-2-ylidenes (163)-(170), l,3-dimesitylimidazoline-2-ylidene (171), 1,3,4-triphenyl-1H-1,2,4-triazole-5-ylidene (172), and their silylene (173) and germylene (174) analogues are stable (in the absence of oxygen and moisture) solids with definite melting points, which can be recrystallized from appropriate hydrocarbon solvents. The exception is carbene (163) which is an unstable liquid however, it is stable in solution. 

The stability of solid dosage forms is usually very susceptible to the moisture content of the atmosphere in the container in which they are stored (see section 4.4.3) A linear relationship between log k and the water vapour pressure for vitamin A palmitate beadlets in sugar-coated tablets has been found. Similarly, a linear relationship between the logarithm of the rate constant for the decomposition of nitrazepam in the solid state and the relative humidity has been established (Fig. 4.f9). The need for consideration of the effect of moisture on stability has been stressed by Carstensen, who stated that stability programmes should always include samples that have been artificially stressed by addition of moisture. One purpose of a stability programme should be to define the stability of the dosage form as a function of moisture content. 

Waste of polyesters and polyamides may have suffered from the hydrolytic depolymerization. Thus, it may be necessary to increase the molecular weight by solid-state polycondensation under high vacuum, or by reactive coupling using such di-functional agents as di-glycidyls. Prior to melt processing, the resins should be dried to less than 0.01 wt% of moisture, re-stabilized and (if compounded with immiscible polymers) compati-bilized. 

Primary container-closure system-related data will need to cover storage, transportation, and use. The choice of materials of construction, their description, and the ability of the container-closure system to protect from moisture and/or light will need to be considered. The compatibility of the container-closure and its contents will need to consider sorption, leaching, and safety. The performance of the container-closure system will also need to be considered in terms of dose delivery from any associated device that is to be supplied as part of the product. Container-closure components will require adequate specifications covering description, identification, critical dimensional tolerances, and test methodology (including pharma-copeial and noncompendial methods). More data are likely to be required for liquid or semi-liquid products than for solid dosage forms. In the latter, product stability data and container-closure system specifications may suffice. 

In addition to the additives used in a formulation to help stabilize the protein to freezing, the residual moisture content of the lyophilized powder needs to be considered. Not only is moisture capable of affecting the physicochemical stability of the protein itself, equally important is the ability of moisture to affect the Tg of the formulation. Water acts as a plasticizer and depresses the Tg of amorphous solids [124,137,138]. During primary drying, as water is gradually removed from the product, the Tg increases accordingly. The duration and temperature of the secondary drying step of the lyophilization process determines how much moisture remains bound to the powder. Usually lower residual moisture in the finished biopharmaceutical product leads to enhanced stability. Typically, moisture content in lyophilized formulations should not exceed 2% [139]. The optimal moisture level for maximum stability of a particular product must be demonstrated on a case-by-case basis. 

Water may be considered as being either bound or unbound, with the unbound portion generally being responsible for reactions requiring moisture as a reactant. In addition to affecting the stability of the formulation, water can also cause strong perturbations in the overall physical properties of the solid. 

The utilization of IR spectroscopy is very important in the characterization of pseudopolymorphic systems, especially hydrates. It has been used to study the pseudopolymorphic systems SQ-33600 [36], mefloquine hydrochloride [37], ranitidine HC1 [38], carbovir [39], and paroxetine hydrochloride [40]. In the case of SQ-33600 [36], humidity-dependent changes in the crystal properties of the disodium salt of this new HMG-CoA reductase inhibitor were characterized by a combination of physical analytical techniques. Three crystalline solid hydrates were identified, each having a definite stability over a range of humidity. Diffuse reflectance IR spectra were acquired on SQ-33600 material exposed to different relative humidity (RH) conditions. A sharp absorption band at 3640 cm-1 was indicative of the OH stretching mode associated with either strongly bound or crystalline water (Fig. 5A). The sharpness of the band is evidence of a bound species even at the lowest levels of moisture content. The bound nature of this water contained in low-moisture samples was confirmed by variable-temperature (VT) diffuse reflectance studies. As shown in Fig. 5B, the 3640 cm-1 peak progressively decreased in intensity upon thermal... 

LIG. 37 Stability map for dairy powders containing amorphous lactose. The critical water activity (0.37 aw) corresponds to the water activity of amorphous lactose with Tg of 24 °C (and a moisture content of 6.8 g water/100 g solids) [reproduced with permission from Roos (2003)]. 

We now turn briefly to the problem of peptide stability in the solid state [8] [88], First, we note that most - if not all - reactions discussed in the previous and subsequent sections can also occur in the solid state, although the kinetics and mechanisms of the reactions can be quite different from those observed in solution. Moisture content, the presence of excipients that act as catalysts, and surface phenomena are all factors whose roles are all-but-im-possible to predict. As a result, each formulation poses a new challenge to pharmaceutical scientists. As a rule, solution data cannot be used to predict the shelf-life of solid formulations, and extrapolating from one solid formulation to another can be misleading. 

---