Physical stability amorphous form

Because of these problems with physical and chemical stability, it is not usual to proceed into development with a candidate drug in such a state. Attempts to crystallize the amorphous phase should always be undertaken, however, it should be borne in mind that amorphous phases, if chemically and physically stable, can have some advantages over the crystalline phase. For example, a stabilized amorphous form of novobiocin was found to be 10 times more soluble and therapeutically active compared to the crystalline form. 

Another physical property that can affect the appearance, bioavailability, and chemical stability of pharmaceuticals is degree of crystallinity. Amorphous materials tend to be more hygroscopic than their crystalline counterparts. Also, there is a substantial body of evidence that indicates that the amorphous forms of drugs are less stable than their crystalline counterparts [62]. It has been reported, for example,... 

Often the stability of a drug in the solid state depends on its physical state (i.e., crystalline or amorphous [8]). If freeze-drying produces an amorphous solid and the amorphous form is not stable, then freeze-drying will not provide an acceptable product. 

Physical stability of compounds in their metastable forms (such as amorphous) can be enhanced by the inhibition or prevention of crystal growth. 

This article provides an overview of the properties and occurrence of amorphous pharmaceutical materials, and outlines their key applications in dosage form development. It describes their characteristics and the fundamental scientific basis for these characteristics. It also highlights the topical issues of chemical/ physical stability and polyamorphism. ... 

The chemical and physical stability of amorphous pharmaceutical materials is controlled by the same basic factors as for crystalline materials [i.e., molecular structure (chemistry), purity (absence of catalysts, chemical reactants, or nucleating agents), molecular orientation (physical form), and molecular mobility (related to temperature)]. For any sample of a given molecular structure and purity, there will be more possible molecular orientations that occur in an amorphous sample than in a crystalline sample. Thus... 

The tendency for amorphous materials to sorb significant amounts of water vapor from their surroundings (Fig. 6) can give rise to a markedly reduced chemical and physical stability relative to the crystalline form of the material. The sorbed water may participate in a chemical reaction... 

As the active substance in a solid solution is in an amorphous state and therefore in a more energetic form, and as its surface area is much greater both in solid solutions and in solid dispersions, the question of its physical and chemical stability arises. The main criterion for physical stability is the extent of recrystallization, which can reduce the bioavailability of the active substance. Surprisingly, a survey of publications in which recrystallization and chemical stability have been investigated reveals only relatively few cases of instability. Table 80 contains a list of publications with stability data for solid solutions of drugs in povidone with a... 

All the active substances investigated so far were converted to the amorphous form by trituration with crospovidone, and this always remained stable in the few trials that have been conducted so far (Table 140). Stability results are available for a much larger number of drugs in coevaporates with crospovidone (Table 141). As all the drugs tested in coevaporates were found to have very good physical stability of their amorphous state, the same can be assumed for triturations. This correlates with similar results obtained with povidone (see Section 2.4.3.2). 

Formulation scientists must consider two types of stability chemical and physical. Physical stability is the change in the physical form of the drug—for example, an amorphous form changing into a crystalline form. The chemical composition remains the same as it was prior to crystallization, but the drug now has different physical properties. Chemical stability is a change in the molecular structure through a chemical reaction. Hydrolysis and oxidation are two common chemical degradation pathways. 

When improvements in the physical stability of a product are needed, choices must be based upon the nature of the problem and the desired goal. One of the first choices made is to use the most stable polymorph of the drug. This may involve an extensive polymorph screening effort to attempt to find the most stable polymorph. If the most stable polymorph is undesirable for some reason (e.g., solubility issues), then avoiding contamination of the desired polymorph with seeds of the most stable polymorph becomes very important. In a product that uses an amorphous form of a drug, it is critical to inhibit crystallization to avoid dramatic changes in stability and solubility. 

Grafting of functional side-groups without forming long polymer chains may be achieved in a similar way by the reaction of activated polymeric materials with low molecular weight compounds carrying functional groups of appropriate reactivity. The physical stabilization of unstable blends of amorphized starch with reactive plasticizers has been achieved by EB-irradiation [11 ]. 

Some new drug substances exist in different crystalline forms that differ in their physical properties. Polymorphism may also include solvation or hydration products (also known as pseudopol5rmorphs) and amorphous forms. Differences in these forms could, in some cases, affect the quality or performance of the new drug products. In such cases, the bioavailabUity stability can be altered requiring choice of specific stable 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 <... 

The crystallization process often follows the mechanism of three-dimensional growth of nuclei after an induction period. Amorphous forms of the same compound made by different methods can have different physical stabilities due to kinetic differences of the crystal nucleation and growth processes [31]. When evaluating the physical stability of amorphous systems, the properties of the crystalline counterpart should also be considered regarding the enthalpic driving force for crystallization and activation energy for nucleation [32]. 

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