Focussed Salt Screening Platform for Drug Solubility Enhancement.

Summary

Within a two week period, by employing a wide range of in-house equipment and a proprietary method, Agenda 1 isolated and identified from a base form of cinnarazine a range of potentially highly soluble salt forms . When tested, all the forms showed improved solubility, with the HCL form showing a 500x increase compared to the base.

Background

On initial synthesis most API’s are isolated in the base form, but these base forms often have poor bioavailability caused by poor solubility. Consequently, investigating the solubility of different salt form options is of critical importance and it is perhaps no surprise that an estimated half of all commercial drugs are administered as salts.

Typical Salt Screens Programs (programs investigating potential conjugate forms) are costly and time consuming, partly because they investigate a very broad range of possible conjugates. Agenda 1 has developed a tightly focussed screen concentrating on a narrow group of counter ions. This limitation means the work can be completed quickly and cost effectively, but it can still produce salt forms with significant benefits over the base.

The following is an example based on the antihistamine drug cinnarazine, the base form of which has limited water solubility.

Resources

Agenda1 has a very wide range of equipment onsite with the majority of the equipment maintained to GMP standards and all of it operated by an experienced team of Agenda1 staff.  The salt screen work was carried out using TGA, DSC, XRPD, HPLC and proton-NMR (the latter operated by Bradford University).

Specifically the work included

XRPD – Analysis was carried out using a Bruker D8 Diffractometer under standard conditions. The resulting diffraction patterns were compared to indicate whether salt formation had occurred and the degree of crystallinity obtained.

TGA and DSC – Both TGA and DSC were carried out using a PerkinElmer Pyris1.

For the TGA, heating began from 5° to 200°C to determine the residual solvent level and the degradation temperature of each sample.

For the DSC, heating began from 25° to 235°C to determine the onset temperature and enthalpy of the melt peak. A single melt would indicate the presence of a fully formed salt.

Application

To ensure an efficient and effective salt screen, Agenda 1 developed and documented a tightly controlled experimental process. This screen was part of a regular program of investments in techniques to support the clients developing drug program.

The screen involved the following steps:

  • A desktop evaluation of the cinnarazine molecule to establish the candidate salts based on the pKa value(s). The stoichiometric ratios of each acid/base reaction were calculated.
  • The solubility determination of cinnarazine in common organic solvents was verified, as both base and acid need to be soluble in a range of solvents. The base was characterised using DSC, XRPD and HPLC.
  • Sighting shot reactions at low mg values were performed using temperature cycling and agitation. The precipitate was then analysed using DSC and XRPD.
  • Scale up reactions to isolate the product was performed and analysed using TGA, DSC, XRPD, HPLC and proton-NMR.
  • The relative solubilities of the salt and base were determined using in house techniques.

Results

The results showed that a well researched, tightly focussed, experimental program can produce valuable data in a short time.  A salt screen was successfully completed within a two week time scale.  Four salt forms were isolated with a good yield, three of which were tested and showed significant solubility enhancement in water compared to the starting base. In particular, the HCL salt demonstrated a 500x increase in solubility.

The following salts were readily isolated in pure form from the five acid/four organic solvent combinations tested, three of which were further tested (see table 1 below):

Cinnarazine HCL (140°C melt). This salt proved to be the most effective improvement in solubility compared to the starting base when assessed in Simulated Gastric Fluid.

Cinnarazine benzene sulphonate (150°C melt)

Cinnarazine fumarate (200°C melt)

Cinnarazine toluene sulphonate

IdentityWater Solubility (mg/mL)Solubility Enhancement Factor
Cinnarazine HCL1.088544
Cinnarazine Benzene Sulphonate0.02613
Cinnarazine Fumarate0.10050
Cinnarazine Base0.002

Table 1: The water solubility determination of cinnarazine and its various salt forms.