Drug Molecule Diflunisal Forms Crystalline Inclusion Complexes with

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Drug Molecule Diflunisal Forms Crystalline Inclusion Complexes with Multiple Types of Linear Polymers Zhi Zhong, Canxiong Guo, Xiaotong Yang, Baohua Guo, Jun Xu, and Yanbin Huang Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b00010 • Publication Date (Web): 18 Jan 2016 Downloaded from http://pubs.acs.org on January 19, 2016

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Crystal Growth & Design

Drug Molecule Diflunisal Forms Crystalline Inclusion Complexes with Multiple Types of Linear Polymers Zhi Zhong,† Canxiong Guo,‡ Xiaotong Yang,† Baohua Guo,† Jun Xu,*,† and Yanbin Huang*,† †

Key Laboratory of Advanced Materials (MOE), Department of Chemical Engineering,

Tsinghua University, Beijing 100084, China ‡

College of Science, Beijing University of Chemical Technology, Beijing 100029, China

Abstract Co-crystals between drug molecules and co-formers have shown great potential to optimize the stability and dissolution profiles of drugs. However, most of the co-formers studied so far are small molecules. Here, we use diflunisal (DIF) as the model drug, and show it could form co-crystals with multiple types of linear polymers in the form of crystalline inclusion complexes (ICs). These drug-polymer ICs were thoroughly characterized with single-crystal and powder XRD, solid-state NMR, DSC and TGA, and showed similar channel structures, but their thermal properties changed with the type and molecular weight (MW) of the guest polymers. In addition, a strategy is proposed to identify the drug candidates with the potential to form ICs with polymers, which may help to expand the range of drug-polymer co-crystals.

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Introduction Pharmaceutical co-crystals are crystalline molecular complexes formed between drug molecules and other pharmaceutically acceptable compounds (i.e., co-formers)1-3, and have recently been studied as a new solid form of drugs for improving the solid and dissolution profiles of drugs4-6. However most of the co-formers in these pharmaceutical co-crystals are small molecules7 such as saccharin and nicotinamide, while only a few drugs were reported to co-crystallize with poly(ethylene glycol) (PEG)8-10. However, drug-polymer co-crystals, or more specifically drug-polymer crystalline inclusion complexes (ICs), may represent a new subcategory of drug solid forms. Like the widely studied ICs formed by small molecular hosts and polymer guests11-17, in a drug-polymer IC the drug molecules form a well-ordered framework with parallel and isolated channels and polymer chains of extended conformations reside in such channels. Compared with small molecular co-formers, which usually form hydrogen bonds with the drug molecules18-20 and hence the co-crystal structures vary with co-formers21-23, it is not necessary for the polymer co-formers to form such specific interactions with drugs, but they should possess suitable chain crosssection sizes to fit in the channels and stabilize the otherwise-maybe-unstable channel framework formed by drug molecules24-26. Therefore, it seems reasonable to hypothesize that different linear polymers may fit in the same channel structure and form isostructural ICs with the same drug. Herein, we demonstrate the formation of crystalline ICs of diflunisal, a non-steroid anti-inflammatory drug (NSAID), with multiple types of linear polymers, including polytetrahydrofuran (PTHF, Mn = 2,900 Da), poly-ε-caprolactone (PCL, Mn = 10,000 Da), poly-4-hydroxybutyrate (P4HB, Mn = 4,000 Da) and poly(butylene adipate) (PBA, Mw = 12,000 Da) (Figure 1).


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Figure 1. Structural formula of (a) DIF, (b) PTHF (n = 40), (c) PCL (n = 88), (d) P4HB (n = 47) and (e) PBA (n = 60). Results and Discussion Co-crystallization between DIF and the guest polymers was carried out in ethyl acetate or acetone solutions (for details please see the Supporting Information, SI). The structural features of DIF-polymer ICs were first characterized by powder X-ray diffraction (PXRD, Figure 2). All four DIF-polymer ICs showed similar diffraction patterns with each other, which were different from that of any known DIF polymorphs (Form I, II, and III) but bore a striking resemblance to the DIF-chloroform solvate, which is known to have a channel structure with disordered solvent molecules residing in isolated channels27. To confirm the formation of DIF-polymer ICs instead of new DIF solvates, thermogravimetric analysis (TGA) and solution 1H-NMR were used to determine the composition of these DIF crystals. As shown in Figure 3, DIF-chloroform solvate showed an obvious weight loss at a temperature range from 80-120 ◦C due to the loss of chloroform, and subsequent weight loss after 160 ◦C due to the loss of DIF itself (Figure 3, compared with DIF Form I). However, for the 4 DIF-polymer ICs, no detectable weight loss was observed on TGA curves before 160 ◦C, indicating no small molecular solvent existed in these samples. In addition, even at 260 ◦C when almost all DIF were lost, there were still 20 % of the initial weight remained, which should be the guest polymers whose decomposition temperatures



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were all higher than 260 ◦C (Figure S1). To further quantify the drug: polymer ratio, these DIF-polymer ICs were dissolved and solution 1H-NMR spectra (Figure S2) were used to quantify the DIF: monomer ratios (Table 1).

Figure 2. PXRD patterns of pure DIF forms (Form I, II and III), DIF-chloroform solvate and the 4 DIF-polymer ICs.


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Figure 3. TGA thermograms of different crystalline forms of DIF measured at a heating rate of 10 ◦C/min. A weight loss of 13.4 % around 100 ◦C for DIF-chloroform solvate is associated with the desolvation process. The residual weights of DIF-polymer ICs above 250 ◦C correspond with the guest polymers. Table 1. Molar ratios of DIF to monomers in the 3 DIF-polymer ICsa

DIF: monomer a

DIF-PTHF

DIF-PCL

DIF-PBA

2.5: 1

4: 1

6: 1

P4HB is a biologically produced polyester and has other components such as P3HB, and

hence the accurate DIF: 4HB monomer ratio in DIF-P4HB IC cannot be determined in this study. Single crystals of two of the DIF-polymer ICs, DIF-PTHF and DIF-PCL, were obtained using oligomers as the guest, and their structures were solved by X-ray diffraction analysis. A summary of the unit cell parameters for DIF-PTHF, DIF-PCL and the previously reported isostructural DIF solvates27-29 is given in Table S1. The guest polymers included in DIF channel lattices were found to be highly disordered in configuration and could not be modeled. Hence they were removed from the structural models using PLATON/SQUEEZE30. It should be noted that, the disorder state of guest molecules in host channels has been commonly observed in crystalline ICs24-29, 31-34, which largely arises from the weak host-guest



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interactions35, 36. The lack of three-dimensional order makes it impossible to accurately determine the configuration of guest molecules through X-ray diffraction analysis, and the possible conformations of guest polymer chains confined in host channels are usually estimated through other approaches, such as FTIR and solid-state NMR11-17, 37-40, as described later.

Figure 4. Molecular packing in (a) DIF-PTHF and (b) DIF-PCL ICs as determined from single-crystal XRD analysis (guest polymers not shown). Oxygen and fluorine atoms are shown in red and yellow colors, respectively. The molecular clusters around a channel are highlighted by the blue wireframes and shown in a space-filling representation in the insets. In DIF-PTHF IC (Figure 4a and Figure S3 and S4), two adjacent DIF molecules formed a dimer via a pair of intermolecular hydrogen bonds between their respective carboxylic groups, while the hydroxyl group on the ortho site formed intramolecular hydrogen bonds. Stacking of the DIF dimers generated isolated, continuous channels along the crystallographic


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b-axis. PTHF chains occupied these channels, and since all the conventional hydrogen bond donors in DIF were already saturated, and there is no hydrogen bond donors in these polymers, it seems reasonable to say that van der Waals interactions between drug and polymer was the dominant interaction to stabilize the DIF channel framework. It should be noted that, the packing mode of DIF molecules in DIF-PTHF IC is almost the same as those in the previously reported isostructural channel-type DIF solvates (e.g. chloroform, hexane, water, etc.)27-29, as clearly evidenced by the overlap of their channel structures (Figure 5) as well as the unit cell parameters (Table S1). Additionally, similar to PTHF chains in DIF channels, solvent molecules in channels of these 3 DIF solvates were also reported to be in a disordered state, whose configurations could not be definitely solved by single-crystal XRD. Similar channel structure was also observed in DIF-PCL IC (Figure 4b and Figure S5-S7). However, a different crystallographic symmetry is adopted by the channel structure in DIF-PCL compared with those in DIF-PTHF and DIF solvates, leading to a slight change in the molecular packing mode as well as a smaller unit cell and shrinkage of the channels in DIF-PCL (Figure S6). This change in channel structure may arise from the stronger interactions between DIF and PCL, e.g. the possible non-conventional C–H⋯O hydrogen bonds41 between the phenyl rings in DIF channels and the ester groups on PCL chains. Single crystals of DIF-P4HB and DIF-PBA ICs have not been obtained yet. However, due to the close similarities in the PXRD patterns of DIF-polymer ICs (Figure 2 and S9), DIF-P4HB and DIF-PBA should also adopt channel structures similar to those in DIF-PTHF and DIF-PCL. Slight differences among the PXRD patterns of these 4 DIF-polymer ICs were noticed, suggesting the fine structures of these channels varied with the guest polymers (Figure S8). The general similarity and fine difference among the 4 DIF-polymer ICs were also evident in their CP/MAS 13C solid-state NMR spectra (Figure S10). The significant differences in

13

C

resonances between pure DIF forms and DIF ICs clearly indicate their different molecular packing modes. While DIF ICs possess close structural similarities, fine differences in chemical shifts can still be observed, as a result of the changes in channel composition as well as channel structure caused by the accommodation of different guest molecules.



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Figure 5. Overlap of the channel structures in DIF-PTHF (green), DIF-chloroform (grey), DIF-hexane (yellow) and DIF-water (purple). Multiple types of disordered guest molecules occupy the cavities as schematically shown with the blue ellipsoid. Due to the disordered state of guest molecules in DIF channels, it is difficult to model the included polymer chains through X-ray diffraction analysis. In this study, CP/MAS

13

C

NMR was used to study the conformations of guest polymers in the channel lattices. As shown in Figure 6,

13

C resonances characteristic of the guest polymers can be clearly

observed in DIF ICs, and show changes to various extent compared with those of pure polymers. Summary of the chemical shift values for the guest polymers in bulk and in ICs was listed in Table 2.

13

C chemical shift changes for a polymer chain can be attributed to

intermolecular packing42 (usually less than ~1-2 ppm), to conformational changes43, 44, or to both of these two effects45 (which can be over ~4 ppm). Since the difference of the chemical shift for each carbon of PCL and PBA is less than 1 ppm upon inclusion, it can be deduced that the conformations adopted by PCL and PBA chains in the isolated DIF channels are very similar to the all-trans, planar zigzag conformations observed in their bulk crystalline materials37,

46, 47

. For PTHF and P4HB, noticeably larger changes (over 1 ppm) in their

chemical shifts suggest that these chain conformations in channels deviates from the all-trans, extended ones in their bulk48, 49. This conclusion is consistent with the extended, nearly all-trans conformation of PCL chains in urea ICs27, in which urea molecules form channels with a diameter (~5.5 Å)11 similar to that of DIF-PCL (~4.7-5.6 Å)50. While for DIF-PTHF, the slightly distorted all-trans, planar zigzag conformation of PTHF chains in urea ICs14 may


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not fit in the larger channels of DIF-PTHF (~4.6-6.5 Å), and an expanded chain conformation is needed.

Figure 6. CP/MAS 13C spectra showing the resonances characteristic of the guest polymers in different DIF-polymer ICs and in their raw materials. The peaks marked with asterisks indicate spinning sidebands. The peaks marked with triangles in the spectrum of P4HB correspond to the small amount of P3HB in the raw material. Table 2. Chemical shift values for guest polymers in bulk and in DIF ICs assignment

δrawa (ppm)

δICb (ppm)

PTHF


∆δ


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Ca1

27.96

26.96

-1.00

Ca2

72.44

71.18

-1.26

Cb1

173.49

173.09

-0.40

Cb2

33.09

33.75

0.66

Cb3

25.66

25.59

-0.07

Cb4

25.66

25.59

-0.07

Cb5

29.05

29.15

0.10

Cb6

65.34

64.91

-0.43

Cc1

174.34

172.33

-2.01

Cc2

28.65

30.06

1.41

Cc3

23.40

24.79

1.39

Cc4

64.94

64.27

-0.67

Cd1

173.37

173.07

-0.30

Cd2

34.11

33.62

-0.49

Cd3/ Cd5

24.36

24.90

0.54

Cd4

63.84

64.15

0.31

PCL

P4HB

PBA

a

δraw: 13C chemical shift of raw materials. bδIC: 13C chemical shift of the guest polymers in DIF

IC crystals. c∆δ: Change in the chemical shift between raw materials and ICs, ∆δ = δIC – δraw.


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The thermal stability of these DIF-polymer ICs was found dependent on the type and MW of the incorporated guest polymers (Figure 7). DIF Form I was reported as the most stable polymorph and showed a melting point at 214 ◦C, while Form II and Form III are metastable forms and transformed to Form I through a solid-solid transition during heating, associated with no or very weak endotherm51. The endotherm around 115 ◦C for DIF-chloroform solvate is assigned to the desolvation process, consistent with the TGA thermogram. During the heating scan, DIF-polymer ICs all exhibited an endothermal event before the final fusion, which was due to the dissociation of the polymer guests, and the simultaneous recrystallization of DIF, as confirmed by PXRD and POM observation (Figure S11-S17). This dissociation temperature varied with the polymer type, probably reflecting the strength of the drug-polymer interactions and the chain mobility itself. The dissociation temperatures were also found to depend on the molecular weight of the guest polymers. For example, decrease of PTHF MW from 2900 to 650 Da caused a significant decrease in the dissociation temperature from 172 ◦C to 151 ◦C, while for DIF-PCL the dissociation temperature decreased from 203 ◦C to 173 ◦C when the PCL MW changed from 10000 to 530 Da (Figure S18 and S19). The chain length effect is similar to that observed in pure polymer crystals52, 53, probably due to the fact that chain ends are defects in both types of crystals, and the defect density changes with polymer MW and also affects the thermal transition temperatures54, 55. These results suggest the properties of drug-polymer ICs can be adjusted by varying not only the chemical structure, but also the chain length of the guest polymers, thus providing a facile way to systematically modulate the thermal stability of drug crystals without substantially altering the crystal lattice.



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Figure 7. DSC thermograms of DIF pure forms, chloroform solvate and DIF-polymer ICs, measured at a heating rate of 10 ◦C/min. The dissociation temperatures are marked by black arrows on the curves. Conclusion We have demonstrated the formation of crystalline ICs between small molecule drug diflunisal and multiple types of linear polymers. Though crystalline ICs between small molecular host and polymer guest (e.g., urea-polymers56, 57, cyclodextrin-polymers58) have been widely studied before, very few such systems were reported in the pharmaceutical field. To the best of our knowledge, griseofulvin8, mavacoxib9, and resorcinol10 are the only known examples and PEG is the only polymer co-former in the literature. Therefore, instead of the current trial-and-error approach, it would be interesting to develop a searching strategy to identify more drug candidates with the potential to form drug-polymer ICs. We here note that, DIF-polymer ICs are isostructural with the previously reported DIF channel-type solvates.


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Similar phenomena were also noticed in the recently reported Griseofulvin-PEG co-crystal8, 59

, as well as in the extensively studied IC systems such as urea60, perhydrotriphenylene

(PHTP)61 and tris(o-phenylenedioxy)cyclotriphosphazene (TPP)62, 63, where the host channels originally filled by different types of solvent molecules can also be occupied by appropriate polymer chains. Therefore, the formation of isostructural channel-type solvates with small molecular solvents may be an indication for drug candidates with intrinsic IC nature, and the capability of accommodating polymer guest of proper cross-sections (Figure 8). With the help of this strategy and the crystal structure database64-66, the short list of promising drug candidates for drug-polymer ICs can be extended to more drug molecules, such as phenylbutazone67, droperidol68, 69 and nevirapine70, and hopefully the drug-polymer ICs will become a general solid form for many drugs. These drugs are currently being studied for their drug-polymer IC formation and the pharmaceutical profiles such as dissolution and stability.

Figure 8. Schematic diagram showing the searching strategy for drug-polymer ICs proposed in this study.



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ASSOCIATED CONTENT Supporting Information Materials and experimental details, crystallographic data, CIF files, molecular packing patterns in single crystals, PXRD patterns, 1H-NMR spectra and CP/MAS

13

C ssNMR

spectra, DSC and TGA data, and POM observations. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Authors Jun Xu, email: [email protected]; Yanbin Huang, email: [email protected]. Notes The authors declare no competing financial interests. ACKNOWLEDGMENT This work was financially supported by the National Natural Science Foundation of China (Grant No. 21374054) and the Sino-German Center for Research Promotion. REFERENCES (1) Aakeroy, C. B.; Salmon, D. J. CrystEngComm 2005, 7, 439. (2) Steed, J. W. Trends Pharmacol. Sci. 2013, 34, 185. (3) Stahly, G. P. Cryst. Growth. Des. 2007, 7, 1007. (4) Sun, C. C. Expert Opin. Drug Deliv. 2013, 10, 201. (5) Williams, H. D.; Trevaskis, N. L.; Charman, S. A.; Shanker, R. M.; Charman, W. N.; Pouton, C. W.; Porter, C. J. H. Pharmacol. Rev. 2013, 65, 315. (6) Babu, N. J.; Nangia, A. Cryst. Growth Des. 2011, 11, 2662. (7) Schultheiss, N.; Newman, A. Cryst. Growth Des. 2009, 9, 2950.


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For Table of Contents Use Only Drug Molecule Diflunisal Forms Crystalline Inclusion Complexes with Multiple Types of Linear Polymers Zhi Zhong, Canxiong Guo, Xiaotong Yang, Baohua Guo, Jun Xu,* and Yanbin Huang*

Synopsis: Drug molecules can form co-crystals with linear polymers in the form of crystalline inclusion complexes (ICs), and their properties are adjustable with the type and molecular weights of the guest polymers.


Drug Molecule Diflunisal Forms Crystalline Inclusion Complexes with

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