Novobiocin amorphous form

The metastable forms are preferred in pharmaceutical preparations due to their higher solubility and dissolution rate e.g. the amorphous form of novobiocin is absorbed readily as compared to its crystalline form. 

Utilizing an amorphous form of an API is not, however, universally desirable. Amorphous compounds are often metastable. As a result, there is a real risk that they will transform to crystalline materials in the final dosage form. Novobiocin again provides a case in point. The amorphous form, in aqueous suspension, will transform on standing into the inactive crystalline form.10 Similarly, the highly soluble metastable crystals of riboflavin revert to less soluble forms if they are washed with water above 10°C.9... 

The amorphous form of a dmg has no crystalline lattice and therefore less energy is required for dissolution, so that the bioavailability of the amorphous form is generally greater than that of the crystalline form. For example, the amorphous form of novobiocin is at least 10 times more soluble than the crystalline form. 

The large hydrophobic compound XIX, even as its hydrochloride salt, is poorly soluble and this is presumably the reason for its poor oral bioavailability. Similar conclusions were drawn several years ago for novobiocin. The acid salt administered at 12.5 mg kg to dogs was not absorbed, but the monosodium salt, which is about 300 times as soluble in water, produced plasma levels of 22 /rg cm after 3 hours. Unfortunately, the sodium salt is unstable in solution. An amorphous form of the acid produced even higher levels of dmg than the sodium salt, illustrating the fact that choice of salt and crystalline form of a dmg substance may be of critical importance. 

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. 

As a rule, metastable polymorphs will tend to have increased solubility and a faster dissolution rate than a stable polymorph. Although four-fold increases in solubility are sometimes observed between the two forms, a 50-100% increase in dissolution rate represents the most usual situation. Riboflavin is an exception. It has three polymorphs with solubilities of 60 mg 1 810 mg 1 and 1200 mg ml. ° When a metastable form is placed in contact with solvents, it can change progressively to the most stable but least soluble form. An example is provided by the acidic and amorphous form of novobiocine, which can hardly be administered as a suspension because of its... 

Table 8.2 Differences in Novobiocin plasma levels as a function of salt form, crystalline form, and amorphous form...

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