Although the application of green chemistry in pharmaceutical development often centers around approaches in the synthesis of the active ingredient, green-chemistry techniques also can be applied to drug-product manufacturing, formulation development, and drug delivery. One such example is spray-dried solid amorphous dispersion technology based on hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a green drug-delivery technology. The approach, which is used by Bend Research (Bend, OR), a drug-delivery technology firm, was an entry in the 2010 US Environmental Protection Agency Presidential Green Chemistry Challenge Awards. Entries for the awards apply green-chemistry technology and were announced in late June (1).

HPMCAS is an amphiphilic polymer. Its hydrophobic regions can interact with low-solubility drug molecules, and its hydrophilic regions allow the drug–HPMCAS structures to form stable colloids in aqueous solutions. HPMCAS forms amorphous dispersions with low-solubility drugs for use in solid oral dosage forms (1). Bend Research uses HPMCAS spray-dried dispersions (SDDs) as a solubilization strategy for poorly water-soluble drugs.

SDDs are single-phase amorphous molecular dispersions of a drug in a polymer matrix, which provide several benefits as a solubilization technique. They enhance the oral absorption of poorly water-soluble compounds by attaining and sustaining a supersaturated concentration of the drug in the gastrointestinal tract. They also may be applied to a wide range of insoluble compounds with various physicochemical properties. SDDs are also physically stable, which allows for long-term storage in various conditions without amorphous phase separation or crystallization of the drug (2).

The HPMCAS–SDDs also provide an efficient drug-delivery mechanism. The drug as an SDD is in a high-energy state compared with the crystalline drug, and when placed in an aqueous solution, SDDs dissolve in a concentration of drug above the solubility of its lowest-solubility crystalline form. The higher concentration of drug facilitates the rapid absorption (2). The improved bioavailability of the low-solubility drug reduces the amount of active pharmaceutical ingredient (API) needed for therapeutic results, thereby creating an efficient drug-delivery mechanism. The more economical use of the API is an overall benefit as it reduces the need for additional chemical production of a given API.

More than 400 drug candidates have been formulated successfully as HPMCAS–SDDs. Twenty-eight compounds have advanced to clinical development (1). The HPMCAS–SDD approach was used in the formulation of torcetrapib, a drug developed by Pfizer (New York) as a potential successor to Lipitor (atorvastatin) until Pfizer stopped Phase III development (3).

The HPMCAS–SDD technology can be applied to various regulatory filings. In December 2009, Bend Research reported that a reference Type V Drug Master File (DMF) for HPMCAS could be used for regulatory filings with US Food and Drug Administration, according to a December 2009 Bend Research press release. A letter of authorization allows FDA to reference the Type V DMF for investigational new drug, new drug, and abbreviated new drug applications.

The Type V DMF for HPMCAS was filed with FDA in 2005 by Pfizer, which was the sponsor of Bend Research's work investigating the use of HPMCAS to improve drug solubility. This Type V DMF contains supplemental nonclinical safety data—including absorption, distribution, metabolism, and excretion data—to support chronic and high-dosage use of HPMCAS as an excipient for human oral delivery. The Type V DMF supplements the DMF filed by Shin-Etsu Chemical (Tokyo) and provides additional data to support the use of HPMCAS in SDDs for improving oral drug bioavailability.

Sources

1. EPA, The Presidential Green Chemistry Challenge Awards Program: Sum mary of 2010 Award Entries and Recipients (EPA, Washington, DC, 2010).

2. D. T. Friesen, Mol Pharm. 5 (6), 1003–1019 (2008).

3. A. Thayer, Chem. Eng. News 88 (22), 13–18 (2010).