The manufacturing process for many pharmaceuticals is hindered by the fact that the organic compound, which is the active ingredient, has handling difficulties during the manufacturing process and may impart undesirable properties to the final drug or dosage form. In addition it can be difficult to control the polymorphic form of the active pharmaceutical ingredient throughout the manufacturing process.
For pharmaceuticals in which the active ingredient can exist in more than one polymorphic form, it is particularly important to ensure that the manufacturing process for the active ingredient affords a single, pure polymorph with a consistent level of polymorphic purity. If the manufacturing process leads to a polymorph with varying degrees of polymorphic purity and/or where the process does not control polymorphic interconversion, serious problems in dissolution and/or bioavailability can result in the finished pharmaceutical composition comprising the active ingredient.
Vorinostat, represented by structural formula (I) and chemically named as N-hydroxy-N′-phenyl-octanediamide or suberoylanilide hydroxamic acid (SAHA), is a member of a larger class of compounds that inhibit histone deacetylases (HDAC). Histone deacetylase inhibitors (HDI) have a broad spectrum of epigenetic activities and vorinostat is marketed, under the brand name Zolinza®, for the treatment of a type of skin cancer called cutaneous T-cell lymphoma (CTCL). Vorinostat is approved to be used when the disease persists, gets worse, or comes back during or after treatment with other medicines. Vorinostat has also been used to treat Sézary's disease and, in addition, possesses some activity against recurrent glioblastoma multiforme.

Vorinostat was first described in U.S. Pat. No. 5,369,108, but no polymorphic data was mentioned. Five crystalline forms of vorinostat, designated forms I to V respectively, were disclosed in documents US 2004/0122101 and WO 2006/127319. However, the five forms disclosed in these documents suffer from several disadvantages which do not make them ideal forms for pharmaceutical development. In particular, the disadvantages associated with the prior art forms I to V include discolouration, polymorphic impurities and instability. The prior art processes to prepare forms I to V, and in particular form III, suffer from the disadvantages of being inconsistent and difficult to reproduce, and they produce polymorphically impure products. The prior art processes are particularly inconvenient for large scale production.
If crystalline forms are made with polymorphic impurities, this causes instability and it can accelerate significant interconversion to another polymorphic form. Therefore it is crucial to produce crystalline forms with very high polymorphic purity to avoid this interconversion.
In view of the importance acquired by vorinostat for the treatment of cancer, there is a great need for developing an alternative, relatively simple, economical and commercially feasible process for the synthesis of vorinostat crystalline forms with commercially acceptable yield, high polymorphic purity and polymorphic stability.