Saccharin Salts of Active Pharmaceutical Ingredients, Their Crystal Structures, and Increased Water Solubilities Rahul Banerjee,† Prashant M. Bhatt,† Nittala V. Ravindra,‡ and Gautam R. Desiraju*,†
CRYSTAL GROWTH & DESIGN 2005 VOL. 5, NO. 6 2299-2309
School of Chemistry, University of Hyderabad, Hyderabad 500046, India, and Informatics Division, GVK Biosciences Private Limited, 6-3-1192, Begumpet, Hyderabad 500016, India Received April 4, 2005
ABSTRACT: Salts of active pharmaceutical ingredients (APIs) have been traditionally used in drug formulations because of improved properties with respect to solubility, stability, or bioavailability. Saccharin has been used as an acid for salt formation with APIs in a few cases hitherto. In this paper, we have explored the generality of this property and have isolated saccharinates of quinine, haloperidol, mirtazapine, pseudoephedrine, lamivudine, risperidone, sertraline, venlafaxine, zolpidem, and amlodipine. These salts have been characterized with singlecrystal X-ray methods. The structures contain many hydrogen bonds of the O-H‚‚‚N(-), N(+)-H‚‚‚N(-), N(+)-H‚‚‚O, N-H‚‚‚O, O-H‚‚‚O and N-H‚‚‚N type, with auxiliary C-H‚‚‚N(-) and C-H‚‚‚O interactions. These saccharinates are mostly very soluble in water when compared to the free base. Additionally, aqueous solutions of these API saccharinates are of moderate pH. Both these properties may be advantageous in the pharmaceutical industry. In general, most saccharinates would appear to have high water solubility, and this follows from the molecular structure of the anion, which is donor-poor and acceptor-rich in terms of hydrogen-bonding functionalities. If an API of insufficient basicity is treated with saccharin, it may form a hydrogen-bonded cocrystal wherein proton transfer from saccharin to the API does not take place. This phenomenon was found in the cocrystal saccharin-piroxicam. Introduction Solid dosage forms of a drug are desirable because of ease of handling and lower production and storage costs.1 An understanding of the solid-state properties of crystalline and amorphous forms of an active pharmaceutical ingredient (API) are therefore extremely important in the development of a new drug.2 Accordingly, there has been a tremendous impetus to identify novel polymorphs, solvates (pseudopolymorphs), salts, and cocrystals of APIs.3 These variations amount to extensions of pharmaceutical space and have both scientific and legal importance. The scientific importance arises from the fact that new API variants are designed to have better solubility, stability, and/or bioavailability. The legal significance arises from the fact that novel polymorphs, solvates, cocrystals, and salts can be used by industry to introduce generic versions of a drug in the regulated market. These matters are of great concern to innovator and generic pharmaceutical companies worldwide.4 Solubility and bioavailability of an API are important, if not always directly related, properties. APIs have been formulated as salts to change the solubility (increase or decrease) and/or obtain better bioavailability, among other reasons. An estimated half of all drug molecules used in medicine are administered as salts so that the formation and the selection of a suitable salt for a drug candidate are recognized as essential steps in the preclinical phase of modern drug development.5,6 Saccharin (pKa 2.2) has been used in the past as an acid (salt former) in the pharmaceutical industry, but the * To whom correspondence should
[email protected]. † University of Hyderabad. ‡ GVK Biosciences Private Limited.
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literature is scanty. It has been reported that the alkaloid vincamine is rendered more soluble by salt formation with saccharin.7 There is also a report that an API saccharinate (buspirone saccharinate) is less soluble than the hydrochloride, and this was claimed as a desirable property.8,9 On the converse side, saccharinate formation of an API was an unintended consequence resulting in a recall of a commercial product. Midazolam hydrochloride was formulated with saccharin in an attempt to sweeten the product for pediatric medication.10 Midazolam saccharinate, with a lower solubility than the hydrochloride, precipitated, rendering the formulation unacceptable. In view of the limited literature on API saccharinates, we studied and recently reported the crystal structures, solubility, and solution pH characteristics of four of these salts.11 The present paper extends these results to seven more APIs of current interest and establishes the general use of saccharin as an acid in pharmaceutical chemistry (Scheme 1). Experimental Procedures Sample Preparation and Crystallization. The APIs were obtained as complimentary samples from local pharmaceutical companies. Saccharin was purchased from Loba chemicals and recrystallized from acetone prior to use. Saccharinate salts of APIs were prepared by taking the appropriate quantities of the API and saccharin and cocrystallizing from 1:1 CHCl3MeOH. Partial to total conversion to the respective saccharinate was also obtained when a dry mixture of appropriate quantities of the API and saccharin were hand ground in a mortar and pestle (typically 50-300 mg were ground for time periods ranging from 15 min to 1 h). In most cases, this latter procedure led to
10.1021/cg050125l CCC: $30.25 © 2005 American Chemical Society Published on Web 09/10/2005
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Crystal Growth & Design, Vol. 5, No. 6, 2005
Scheme 1. APIs in This Study as Found in Their Saccharin Adduct (Cation or Neutral)
mixtures of polymorphs, hydrates, and/or amorphous forms.12 Since the main objective of this study was not to characterize these variations but rather to study the crystal structures and solubility of the saccharinate salts of APIs, analysis of these ground mixtures was deferred. Melting points for the recrystallized API saccharinates were obtained by differential scanning calorimetry (DSC) (Mettler Toledo Star and Mettler TA models) and are given in Table 1, along with other relevant properties. See Supporting Information for the DSC traces.
Banerjee et al.
IR Spectroscopy. A good indication for API saccharinate formation is obtained from the bathochromic shift in the CdO stretching frequency (1720 cm-1 in saccharin to around 1690 cm-1 in the salts). We note that for the piroxicam saccharin cocrystal, the band at 1720 cm-1 was shifted hypsochromically to 1734 cm-1, indicating that salt formation had not taken place. Subsequent X-ray analysis showed that this API is an outlier forming a cocrystal with saccharin rather than a salt. X-ray Crystallography. X-ray diffraction intensities for the API saccharinates were collected at 100 K (Bruker Cryosystems cooler) on a Bruker SMART 4K CCD diffractometer (Bruker Systems Inc.) using Mo KR X-radiation.13 The crystal data of sertraline saccharinate was collected additionally at room temperature (see discussion for the reason for so doing). Data were processed using the Bruker SAINT package14 with structure solution and refinement using SHELX97 (Sheldrick, 1997).15 The structures of all the compounds were solved by direct methods and refined by full-matrix least-squares on F2. H-atoms were located from the difference Fourier map in all 11 structures and refined freely with isotropic displacement parameters. Crystal data and details of data collections, structure solutions, and refinements are summarized in Table 2, and full data have been deposited with the Cambridge Crystallographic Data Centre as deposition No. CCDC 267329267336. Copies of the data can be obtained, free of charge, on application to the CCDC, 12 Union Road, Cambridge CB2 lEZ UK (fax: + 44 (1223) 336 033; e-mail:
[email protected]). Table 3 gives the hydrogen-bond metrics in the crystal structures. X-ray Powder Diffraction. This technique is required to confirm that the bulk material obtained from cocrystallization, and which would be subsequently used for solubility measurements, is identical to the single crystal for which the structure has been determined. Samples were prepared by grinding the recrystallized material, and powder X-ray diffraction (PXRD) data were recorded on a Pnalytical 1830 (Philips Systems Inc.) diffractometer using Cu KR X-radiation at 35 kV and 25 mA. Diffraction patterns were collected over a range of 5-40 °2θ at a scan rate of 1° 2θ min-1. The software Powder Cell 2.3 was used for Rietveld refinement.16 Figure 1 shows a comparison of the experimental and theoretical powder patterns after Rietveld refinement, of lamivudine saccharinate as a representative case. The other API saccharinate powder patterns are given in Supporting Information. Solubility Determination. The shake-flask method was used to determine the equilibrium solubility.17 An excess of sample was taken in double-distilled water, and the resulting suspension was shaken for 24 h at room temperature. The aim was to form a saturated solution, as indicated by the observation of surplus undissolved material. After equilibration, the sample was filtered, and the concentration of the compound in the filtrate was quantified using UV spectroscopy on a Shimadzu UV-VS spectrophotometer after appropriate (1000-2000-fold) dilution. Thus, the thermodynamic solubility rather than a kinetic solubility was determined. The risk of obtaining a supersaturated solution is low in this method, and, in addition, the solubility of the stable form of the substance examined has been
Saccharin Salts of Active Pharmaceutical Ingredients
Crystal Growth & Design, Vol. 5, No. 6, 2005 2301
Table 1. Salient Properties of Selected APIs and Their Saccharinates API
name
marketed product
quinine haloperidol mirtazapine pseudoephedrine
quinine sulfate haloperidol mirtazapine pseudoephedrine hydrochloride lamivudine risperidone sertraline hydrochloride venlafaxine hydrochloride zolpidem tartrate amlodipine besylate piroxicam
lamivudine risperidone sertraline venlafaxine zolpidem amlodipinea piroxicamb
tradename
disease treated
pKa
Log P (octanol/ water)
API saccharinate
solubilityc (mg/mL) API
marketed product
m.p. (°C)
solubility (mg/mL)
pH
malaria schizophrenia clinical depression nasal congestion
Quinine 5.1 Aloperidin 8.3 Remeron Sudafed 9.8
3.40 3.23 7.10 0.90
