Transformations among the New Solid-State Forms of Clindamycin

Oct 22, 2013 - An experimental study is undertaken to establish a transformation screen for the solid-state forms of clindamycin phosphate. The experi...
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Transformations among the New Solid-State Forms of Clindamycin Phosphate Yuanyuan Ran,†,∥ Weibing Dong,‡,∥ Songgu Wu,† Jingkang Wang,† and Junbo Gong*,†,§ †

State-Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P. R. China ‡ Department of Chemistry, School of Science, Tianjin University, Tianjin 30072, P. R. China § Tianjin Key Laboratory of Modern Drug Delivery and High Efficiency, Tianjin University, Tianjin 30072, P. R. China S Supporting Information *

ABSTRACT: An experimental study is undertaken to establish a transformation screen for the solid-state forms of clindamycin phosphate. The experimental study results in six novel crystalline forms: two solvates (with ethanol/water, methanol/water), one hydrate (Form III), and three polymorph forms. Further, all solid-state forms are characterized by various analytical techniques such as X-ray diffraction, differential scanning calorimetry, etc. Two polymorph forms (IV and VI) are selectively prepared by desolvation of the solvates (I and V). The solid-state desolvation results in the appearance of delamination of the 2D layers. Moreover, polymorph IV shows a clear polymorphic transition to a new polymorph form (polymorph II) above 165 °C. Phase transformations of the solid-state forms were also established by slurry conversions at 25 °C. These experiments suggest the reversible relationship between solvate I/V and hydrate Form III at different solvent mixtures. Through the aqueous dissolution test, it is also judged that polymorph II, IV, VI can transform to Form III in water at 25 °C. The conversion relationships among the six solid forms are illustrated.

1. INTRODUCTION The formation of solvates, hydrates, and polymorphs is important for active pharmaceutical ingredients (APIs).1,2,6 Solvates are generally known as molecular adducts containing a solute compound and a solvent in the same crystal lattice, and hydrates are the particular type of solvate when the solvent is water.2,3 While polymorphs contain the same chemical composition in more than one crystalline modification.4,5 Commonly different solid-state forms can display different physicochemical or mechanical properties (e.g., solubility, tablet) to improve the bioavailability.6,7 So there is growing interest in obtaining new solid-state forms and confirming the most commercial form or thermodynamical stable form.8,9 Both the desolvation of solvates and polymorphic transformations are allowed for the preparation of new solid-state forms.10,11 For example, thiamine hydrochloride forms a monomethanolate form, upon desolvation, and the monomethanolate form can transform to the hemihydrates form or anhydrate form under certain conditions.12 Another experimental search resulted in nine crystalline forms of β-resorcylic aid and confirmed the relationship among the solid forms.1 As a result, the discovery and characterization of solvates, hydrates, and polymorphs are crucial in the development of the drug product.13−16 Clindamycin phosphate shown in Figure 1 is a semisynthetic antibiotic drug which is highly effective against Gram-positive and Gram-negative anaerobic pathogens and widely used in clinical applications.17,18 The polymorphism and pseudopolymorphism of clindamycin phosphate was rarely reported; only a hydrate of clindamycin phosphate was found.19 In the present study, two previously unknown solvates, solvate I (ethanol/ water) and solvate V (methanol/water), one novel hydrate, © 2013 American Chemical Society

Figure 1. Chemical structure of clindamycin phosphate.

Form III, and three new polymorphs, polymorph II, IV, VI of clindamycin phosphate, were discovered and characterized by various analytical techniques such as powder X-ray diffraction, single-crystal X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. Especially the desolvation mechanism of solvate V has been explored. Furthermore, the thermodynamic stability relationship and the propensity of transformation among the pseudopolymorphs and polymorphs when exposed to various conditions were studied. Studying the transformations among the new solid-state forms of clindamycin phosphate aims at screening the most commercial form. Based on this study, further research is required to find the commercial form or thermodynamically stable form.

2. EXPERIMENTAL SECTION 2.1. Materials. The raw clindamycin phosphate (solvate I/ polymorph II mixture, chemical purity ≥99.5%) provided by Received: August 26, 2013 Published: October 22, 2013 1445

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Table 1. Methods for preparation of different solid forms of clindamycin phosphate solid forms of clindamycin phosphate

method of preparation

solvate I polymorph II hydrate form III polymorph IV solvate V polymorph VI

cooling crystallization from ethanol/water mixtures heating of polymorph IV in a sealed glass vial kept at 165−170 °C for 3 h slurry experiments of solvate I/V in aqueous solution at 25−50 °C for 3 days heating of solvate I in a sealed glass vial kept at 85−90 °C for 3 h cooling crystallization from methanol/water mixtures heating of solvate I in a sealed glass vial kept at 79−80 °C for 3 h

Zhejiang Hisoar Pharmaceutical Co. Ltd., China was used without further processing or purification. Solvents (methanol and ethanol) were of analytical grade. Deionized water was prepared in our lab and used throughout. Two different solvates (solvate I/V), one hydrate (Form III), and three polymorphs (polymorph II, IV, VI) of clindamycin phosphate were prepared by methods described in Table 1. Solvates I/V were obtained by cooling crystallization processes from an ethanol/ water or methanol/water mixture. The hydrate Form III was crystallized from aqueous solution. Bulk samples of polymorphs II, IV were prepared by heating solvate I at approximately 170 and 90 °C respectively. Polymorph IV is the product of desolvation of solvate I and transforms to polymorph II at high temperature. The bulk sample of polymorph VI was prepared by heating solvate V at approximately 79 °C. 2.2. Characterization of Solid Forms. In order to characterize the new solid-state forms, standard techniques (PXRD, SXRDD, SEM, DSC, TGA, Karl Fisher Titration, Polarized-Light Microscopy, Hot-Stage microscopy) were used. The details for each analytical technique were described in the Supporting Information. 2.3. Slurrying Experiments. The pseudopolymorph transformation was performed using a slurring experiment at 25 °C. Solvate I and solvate V were added to a saturated aqueous solution respectively, and the suspensions were stirred for 30 h, with powder diffraction data collected on a wet sample at different sampling times. The solution-mediated transformation of Form III was performed by slurrying in saturated water and ethanol or methanol mixtures respectively, while monitoring by a polarized-light microscope over a period of 5 h. 2.4. Dissolution Test. The aqueous solubilities of polymorphs II, IV, VI and Form III were determined gravimetrically. The experimental setup consists of a thermostated water bath equilibrated at 25 °C, standing on a serial magnetic stirrer. Round-bottomed glass tubes with a Teflon-coated magnetic stirrer were filled with accurately 10− 15 mg of each crystalline solid. Subsequently 30 mL of deionized water were added. After the predetermined time, a sample of the clear saturated solution is transferred with a preheated syringe through a 0.45 μm membrane filter into a previously weighted sample vial. The vial had Teflon septums to ensure no evaporation of the solvent throughout the weighing procedure. The mass of the sample vial with the saturated solution is measured. Then the septums are removed, and the solvent is allowed to evaporate in an air oven at 40 °C for approximately 48 h; at this point the constant “dry residue” mass is determined. Then the concentration of the solid forms was subsequently determined at different experimental times.

Figure 2. PXRD patterns of the solid forms of clindamycin phosphate.

peaks of solvate I (5.3° and 10.6° 2θ), solvate V (5.8° and 7.9° 2θ), hydrate Form III (4.8° and 11.0° 2θ), polymorph II (5.6° and 13.8° 2θ), polymorph IV (5.4° and 9.6° 2θ), polymorph VI (5.5° and 14.4° 2θ) are indicated. A TGA thermograph indicates 12.7−12.9% mass loss of solvate I (Figure S1) and, through water content analysis, solvate I contains 7.8−8.0% water, so water and ethanol molecules may exist in the crystal lattice of solvate I simultaneously. A TGA thermograph shows 6.6−7.0% weight loss of hydrate Form III (Figure S3), so about two water molecules existed in the crystal lattice of Form III. Another TGA thermograph shows 10.2−10.4% weight loss of solvate V (Figure S5); this thermal event corresponds to desolvation beginning at room temperature, as the calculated value for one methanol and two water molecules of solvate V is 11.8%. No weight loss is observed in the TGA thermographs of polymorphs II, IV, and VI (Figures S2, S4, S6). Figure 3 shows the SEM micrographs of the solid forms. Form III could be

3. RESULTS AND DISCUSSION 3.1. Characterization of Clindamycin Phosphate Crystal Forms. Figure 2 shows the XRPD patterns of solvates I/V, Form III, and polymorphs II, IV, VI. The characteristic

Figure 3. SEM micrographs for solid forms of clindamycin phosphate. 1446

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The polymorph VI was obtained after the desolvation of solvate V over the temperature range 70−80 °C. HSM was used to analyze the thermal behavior of solvate V at a constant heating rate of 10 °C/min (Figure 5). Upon heating, no change was observed until 70 °C. Upon further heating the lamination and defects were formed as the result of the desolvation of solvate V. Heating was stopped at 105 °C, and the crystal delaminated and transformed to polymorph VI characterized by PXRD. DSC data verified the results obtained by HSM. Figure 6 shows the results of the DSC profile upon desolvation of

easily distinguished by its distinct needle morphology. Since polymorph IV and polymorph VI were obtained via desolvation of solvate I and solvate V, and polymorph IV transformed to polymorph II upon heating, crystal crushing was visible for polymorphs II, IV, and VI. 3.2. Phase Transformation upon Desolvation of Solvate V to Polymorph VI. Solvate V crystallizes in the monoclinic space group P21. The centrosymmetric unit of the structure has two host molecules lying on the inversion center with four water molecules and two methanol molecules (Figure 4a). Crystallographic data for solvate V is summarized in Table

Figure 6. DSC traces for solvate V and polymorph VI.

solvate V. The melting points and heats of fusion established for solvate V and polymorph VI are listed in Table 2. As shown in Figure 6, the desolvation and phase change occurred at 79.7 °C.

Figure 4. (a) Crystal packing feature of solvate V. (b) The hydrogen bond interactions to form parallel layers to the b-axis.

S1. In the crystal lattice of solvates, the solvent molecules can serve in different roles,20,21 such as participation in hydrogen bondings to form molecular networks of the lattice structure; as the ligands completing the coordination around a metal ion and facilitating packing arrangements; or filling space in the unit cell with weak interactions between host and guest molecules. Apparently, in the crystal lattice of solvate V, the host and solvent molecules aggregate themselves in layers (Figure 4b) and form a molecular chain along the b axis via hydrogen bonding interactions, and the result is 2D layers formed in the ab plane.

Table 2. DSC data for solvate V and polymorph VI solid forms

onset temp Tt (°C)

ΔHt (J/g)

79.65

74.07

solvate V peak A solvate V peak B polymorph VI peak B

onset temp Tf (°C)

ΔHf (J/g)

194.15 195.60

43.59 30.88

Figure 5. HSM images taken at different temperatures during heating of solvate V at 10 °C/min. 1447

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The desolvation mechanism of solvate V could be formulated from the solid state structure and thermal analyses; several mechanisms for dehydration have been covered by some literature. Similar with the dehydration, the desolvation from solvate V to polymorph VI has two steps. The first step involves the release of guest molecules (one methanol molecule and two water molecules). The second step concerns the reorganization of the desolvated material. When the guest molecules escaped, the 2D layers formed in the ab plane ultimately experienced delamination. Both the SEM micrographs and HMS images support this assumption. Due to the first removal of the guest molecule step, the hydrogen bond has been damaged, so each layer lost some inner connection. At the same time the second reorganization step occurred, with each layer split. Figure 7 is expounded on the whole desolvation mechanism. Figure 9. DSC traces for solvate I, polymorph II/IV.

DSC trace of polymorph II shows a small melting point at 185 °C, as the melting and decomposition section was very close, the melting peak was not very sharp and clear. Meanwhile from the traces of solvate I and polymorph IV, the melting point almost disappeared, as polymorph IV might proceed to decomposition before melting or the two processes overlap. At the beginning of the DSC experiment, both solvate I and polymorph IV had a wide endotherm peak, which resulted from the easy moisture absorption of solvate I and polymorph IV. The desolvation mechanism of solvate I to polymorph IV is similar to the course of solvate V to polymorph VI. The SEM micrographs show the typical distinctions among solvate I, polymorph II, and polymorph IV; the cracks and defects in the crystal surface indicate the desolvation process. Meanwhile the HSM images which were taken at different temperatures during heating of solvate I showed a similar desolvation with solvate V. 3.4. Solvent-Mediated Transformation among the New Solid-State Forms. Through the slurry experiments and the aqueous dissolution test, the solvent-mediated transformation among the new solid-state forms of clindamycin phosphate has been studied. 3.4.1. Solvent-Mediated Transformation between Solvate I/V and Form III. Slurry experiments were designed to explore the phase transformation between solvate I/V and Form III at room temperature. Figure 10 showed snapshots taken during the solvent-mediated transformation of Form III → solvate I and Form III → solvate V at room temperature. The sequence of microscopic images in Figure 10a showed that needle-like Form III crystals were slurried in ethanol/water mixtures, until 30 min after the beginning of the experiment; 15 min later solvate I nucleated and crystals were grown, the small plate-like crystals agglomerated to particles, needle-like Form III crystals dissolved and disappeared in Figure 10a. At last Form III transformed to solvate I completely. This transition phenomenon could also be observed in methanol/water mixtures; Form III transformed to solvate V as shown in Figure 10b. The phase transformations of solvate I → Form III and solvate V → Form III were studied by the slurry of solvates I/V in water at room temperature. The powder diffraction data gave the results shown in Figure 11. In Figure 11a, only the characteristic peaks of solvate I were presented at t = 0 min, and 15 min later characteristic peaks of Form III were evident. At last, after 30 h, only the characteristic diffraction peaks of Form

Figure 7. Desolvation mechanism of solvate V.

3.3. Phase Transformation among Solvate I, Polymorph IV, and Polymorph II. The transformation route from solvate I to polymorph IV and then to polymorph II was explored. Upon heating on HSM, solvate I was transformed to polymorph IV first and then to polymorph II characterized by PXRD (Figure 8). With a heating rate of 10 °C/min, the crystal of solvate I became dark at ∼75 °C.

Figure 8. HSM images taken at different temperatures during heating of solvate I at 10 °C/min.

Figure 9 shows a DSC trace of a representative solvate I batch, where the first endotherm peak with an onset of 92.2 °C corresponds to the desolvation of solvate I. This desolvation made solvate I transform to polymorph IV characterized by PXRD. Then at ∼175 °C a small exothermic peak appeared, indicating crystallization of a different crystalline phase, followed by cooling, with the polymorph II achieved. The 1448

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Figure 11. PXRD results of the slurry transformation of solvate I/V to Form III. (a) Solvate I to Form III transformation at 25 °C. (b) Solvate V to Form III transformation at 25 °C.

Figure 10. Images during solvent-mediated phase transformation of Form III to solvate I/V. (a) Form III to solvate I at 25 °C in ethanol/ water mixture. (b) Form III to solvate V at 25 °C in methanol/water mixture.

III were observed. Figure 11b shows the transition from solvate V to Form III. Similar results have been shown. 3.4.2. Dissolution Test. The aqueous dissolution test of Form III and polymorphs II, IV, VI were inspected. PXRD was carried out to identify the undissolved powder before and after the dissolution analysis. A remarkable observation is that the pattern of the undissolved sample of polymorphs II, IV, and VI is identical to the pattern of Form III in some distinct peaks, while the pattern of the undissolved sample of Form III remains the same. This indicated that a significant portion of polymorphs II, IV, VI transformed into Form III during the aqueous solubility analysis. To study the possible solventmediated transformation during a dissolution test, a series of concentration measurements were made after a designated time. These results are shown in Figure 12. Meanwhile Figure 12 shows that although there is a gap among different solid forms regarding the equilibrium solubility value, all the solid forms have the same aqueous solubilities

Figure 12. Aqueous dissolution test of Form III and polymorphs II/ IV/VI as a function of time at 25 °C.

after 48 h. This is due to the solvent-mediated transformation among polymorphs II, IV, VI to Form III in water at room temperature. 1449

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4. CONCLUSIONS Clindamycin phosphate exhibits complex polymorphism behavior. The experimental search has resulted in six new solid-state forms (two solvates, one hydrate, and three polymorphs). The work presented here also clearly defines the relationship among the different solid-state forms, with thermal analysis helping to establish the stability of the solidstate forms. Solvates I/V and hydrate Form III were achieved by solution crystallization (cooling method), and polymorphs IV and VI can be selectively prepared by desolvation of solvate I and V respectively; the solid-state desolvation mechanism results in the appearance of delamination of the 2D layers. Moreover, polymorph IV showed a clear polymorphic transition to polymorph II when heated by DSC. Phase transformations of the solid-state forms were also established by slurry conversions at room temperature. These experiments suggest the reversible relationship between solvates I/V and hydrate Form III at different compositions of organic solutions and water; solvates I/V transform to Form III in water, while hydrate Form III can transform to solvates I/ V in an ethanol/water or methanol/water mixture. During dissolution testing in water, it also was judged that the polymorphs II, IV, VI could transform to Form III in pure water at room temperature. Hence Scheme 1 is used to

Microscopy, Hot-Stage microscopy. This material is available free of charge via the Internet at http://pubs.acs.org.

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Corresponding Author

*E-mail: [email protected]. Telephone: 86-22-27405754. Fax: 86-22-27314971. Author Contributions ∥

Y.R. and W.D. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The analysis tools used in this study were supported by the National Natural Science Foundation of China (No. NNSFC 21176 173); Tianjin Municipal Natural Science Foundation (No. 11JCZDJC 20700); and National High Technology Research and Development Program (863 Program No. 2012 AA021202).

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Scheme 1. Interconversion among six forms of clindamycin phosphate

generally define the relationships among the different solid forms of clindamycin phosphate. To gain a clear interconversion between the six solid forms, further research should be carried out.

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AUTHOR INFORMATION

ASSOCIATED CONTENT

S Supporting Information *

X-ray crystallographic information file (CIF) and Check CIF file (PDF) are available for structure solvate V. The crystallographic data of solvate V is summarized in Table S1. The TGA trace for solvate I (Figure S1), polymorph II (Figure S2), Form III (Figure S3), polymorph IV (Figure S4), solvate V (Figure S5), polymorph VI (Figure S6), and the DSC trace for Form III (Figure S7) are illustrated. Also, the details for each analytical technique that was used for characterization of the new solid-state forms are described including PXRD, SXRDD, SEM, DSC, TGA, Karl Fisher Titration, Polarized-Light 1450

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