Poor bioavailability is a problem often faced in the drug development process. It is, in fact, one of the main reasons why companies work with Aptuit and SSCI Inc., its solid state chemistry company. Purdue Pharma brought a compound to SSCI that demonstrated poor water solubility and low in vivo concentrations when tested orally in dogs. In order to improve bioavailability, a more water soluble form of the active pharmaceutical ingredient (API) was required.

After preliminary testing and screening without forming a salt, Aptuit scientists decided that the next course of action to solve this bioavailability problem would be to examine the potential of forming cocrystals for the specific purpose of increasing the dissolution rate. Cocrystallization is a fairly new approach within the pharmaceutical industry that can produce alternative, viable solid forms when a more standard approach of salt and polymorph formation fails to deliver. In the Purdue case, 5 new solid phases were identified and confirmed to be cocrystals. The cocrystal with the most promising physical properties and characteristics was selected for further testing.

In vitro testing, including intrinsic dissolution studies, showed that the cocrystal had a significantly faster dissolution rate than the original API, an approximate 18-fold improvement. A subsequent bioavailability study conducted in vivo with dogs confirmed what was shown in the lab: the new cocrystal developed by Aptuit demonstrated enhanced bioavailability, with a 4-fold improvement over the API.

As a global leader in drug development services, Aptuit has the resources and capabilities to analyze existing drug substances and find potential ways to enhance bioavailability. Through our integrated services offering, we can also provide complete drug development services from API development to pharmaceutics, physical and analytical chemistry, preclinical and clinical technologies and clinical packaging and logistics.

The complete technical details of this project can be found in the following peer-reviewed reference: McNamara, et al. Pharm. Res. 2006, 23, 1888.

The Challenge The compound shown in Figure 1, supplied by Purdue Pharma to SSCI, A Division of Aptuit, was a weakly basic API with an estimated pKa of 0.7. It demonstrated poor water solubility and low in vivo concentrations when administered orally in dogs. Purdue required a more water soluble form to improve bioavailability. Initial salt screening did not produce any crystalline salts.

The Aptuit Solution A cocrystal screen was attempted to identify new forms that would improve the pharmaceutical properties of the Purdue drug candidate. Multiple cocrystallization techniques were applied to the compound, including the Kofler technique (Figure 2), and five cocrystals were found using the following guests: Benzoic acid Fumaric acid Gentisic acid Glutaric acid Salicylic acid

Of these five cocrystals, glutaric acid (Figure 3) was chosen as the development candidate because it demonstrated the most promise. Specifically, glutaric acid’s higher water solubility indicated that it could contribute to an increased dissolution rate when used in a cocrystal, and its melting point suggested that it would remain stable during storage.

X-ray powder diffraction (XRPD) and Raman spectroscopy were two of the analyses conducted on the original compound and the new form. As shown in Figures 4 and 5, the testing confirmed that the techniques used yielded the formation of a new cocrystal.

Further testing was conducted, including differential scanning calorimetry (DSC) and dynamic vapor sorption (DVS) analysis. As shown in Figure 6, the new cocrystal exhibited a unique melting point, distinguishing it from the original compound and glutaric acid.

DVS analysis as shown in Figure 7 indicated that the glutaric acid cocrystal demonstrated little water absorption/desorption and therefore is most likely non-hygroscopic.

Intrinsic dissolution testing of the cocrystal and the original API was conducted to test bioavailability. Figures 8 and 9 demonstrate the improved dissolution rate of the cocrystal over the API, dissolving 18x faster in water, which supports its improved bioavailability.

In vivo testing conducted on dogs confirmed these results (Figures 10 and 11). The cocrystal showed an increase in AUC (area under the curve) of approximately 4x when tested at two doses of 5 and 50 mg/kg. in dogs.

Conclusion

The development and analysis work conducted by Aptuit resulted in the discovery of a new form that demonstrated significantly improved properties over the original API supplied by Purdue Pharma. By using the cocrystal approach, Aptuit was able to identify 5 cocrystals with potential; select the cocrystal candidate with the most promise; test the candidate’s efficacy in the lab; and validate that the new form provided enhanced bioavailability. Finally, it should be noted that because of the breadth of integrated capabilities and services offered by Aptuit, all of this work can be conducted within our own organization, from API development to pharmaceutics to in vivo animal testing. At Aptuit, it’s all about the science.