Isostructural Multicomponent Gliclazide Crystals with Improved

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Isostructural Multicomponent Gliclazide Crystals with Improved Solubility Okky Dwichandra Dwichadra Putra, Etsuo Yonemochi, and Hidehiro Uekusa Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b01279 • Publication Date (Web): 30 Sep 2016 Downloaded from http://pubs.acs.org on October 5, 2016

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Crystal Growth & Design

Isostructural Multicomponent Gliclazide Crystals with Improved Solubility Okky Dwichandra Putra,a Etsuo Yonemochi,b and Hidehiro Uekusaa* a

Department of Chemistry and Materials Science, Tokyo Institute of Technology,

Ookayama 2-12-1, Meguro-ku, Tokyo 152-8551, Japan b

School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41,

Ebara, Shinagawa, Tokyo 142-8501, Japan

Abstract This study focused on pharmaceutical isostructural multicomponent crystals and compared their physicochemical properties. Gliclazide (GLI), a drug used for treating diabetes mellitus, formed isostructural multicomponent crystals with 4-aminopyridine and 3,4-diaminopyridine. The structures of these crystals were determined by single-crystal X-ray structure analysis. These crystals were categorized as salts because they showed proton transfer. The crystal structures revealed a robust one-dimensional hydrogen bond chain of GLI by the crystallographic 21 screw axis along the b-axis and the interaction between these two chains, which includes the co-former, to construct a dimeric structure were crucial to the isostructurality. These salts showed a promising dissolution rate that was higher relative to that of the raw material. Interestingly, although both are isostructural, 4-aminopyridine salt showed a faster dissolution rate than 3,4-diaminopyrdine salt.

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1. Introduction Gliclazide (GLI) is a second-generation sulfonyl urea that is used for treating non-insulin diabetes mellitus.1 GLI is available as oral tablet (80 mg strength and 60 mg strength given as micronized powder) with recommended individual dosage between 40 and 320 mg/ day.2 Although GLI reduces the blood glucose level during both short and long administration, it shows slow absorption rate.3 GLI’s low solubility, especially in an acidic solution, may reduce absorption after oral administration. Thus, GLI’s bioavailability is limited by its solubility.4 GLI does show some advantageous pharmacological properties such as good tolerability, low rate of secondary failure, and diabetic retinopathy.5 Therefore, it remains an important drug for treating diabetes. Several research groups have improved GLI’s solubility using various techniques such as micronization, complexation with β-cyclodextrin, and formation of a solid dispersion.5-7 However, all of these techniques generally have some limitations. In practice, reducing the particle size by micronization to increase the surface area is a good way to improve drug dissolution. However, this approach may be unsuitable, especially when the drugs are tableted.8 In complexation with β-cyclodextrin, some compounds cannot interact strongly with the cavity, resulting in insignificant solubility improvement.9 In a solid dispersion, various types of polymers and sugars are incorporated into drugs. The crystalline drugs are transformed into an amorphous phase.10 However, the amorphous phase is known to be thermodynamically unstable, and it tends to reorder into a crystalline phase; this can affect the quality of the drug. Therefore, all of these techniques are difficult to control in term of a pharmaceutical quality


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system (PQS). Alternatively,

GLI’s

solubility

could

be

improved

by

forming

a

multicomponent crystal. A multicomponent crystal is considered a new entity that would be relatively easier to control in term of a PQS. A multicomponent crystal is a molecular assembly comprising the drug molecule and complementary molecules such as solvents and additives.11 A multicomponent crystal is generally classified into hydrate, solvate, co-crystal, and salt. By controlling how molecules interact within the crystal lattice, the change in physicochemical properties can be understood easily.12-20 Among the four abovementioned types of multicomponent crystals, salts usually show better solubility improvement because of their ionic dissociation capability in a solvent.21-22 The common strategy used to form a stable salt is generally called the pKa rule. The required ∆pKa between a base and an acid is at least three units to form a salt. N of the sulfonyl urea group of GLI has pKa of 1.46 ± 0.11.23 Therefore, according to the pKa rule, the counter-ion should have pKa greater than 4.46 to form a salt. An isostructural salt is a rarely explored class of materials in pharmaceutical

solids,

possibly

because

they

are

rare.24

In

the

pharmaceutical field, isostructurality means producing more than one molecular complex using a common structural blueprint.25-26 In this case, although molecular arrangements are similar, the physicochemical properties can be modified owing to the differences among co-former molecules

and

the

small

packing

difference.

A

pharmaceutical

multicomponent crystal, especially a salt, can be synthesized by



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systematic crystallization screening, in which a common API component is combined with various co-former components having similar molecular structures.

Scheme 1. Chemical structures of (a) GLI, (b) 4-aminopyridine, and (c) 3,4-diaminopyridine.

In this study, we use the pKa rule to prepare GLI salts. The aminopyridine derivatives were explored as an isostructural salt co-former. Single-crystal X-ray structure analyses were performed to elucidate the structure of the salts. To the best of our knowledge, few studies have compared the physicochemical properties of an isostructural salt. Thus, dissolution rate tests were performed to evaluate the change in properties due to isostructurality relative to the intact material of GLI. 2. Experimental 2.1 Materials GLI was purchased from Wako Pure Pharmaceutical Industries, Ltd., and used as received for all processes. Other chemicals were purchased from Nacalai Tesque and used without further purification. 2.2 Synthesis of Gliclazide–4-aminopyridine salt


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The salt was prepared via co-grinding and diffusion methods. For co-grinding, an equimolar mixture of GLI (323.4 mg, 1 mmol) and 4-aminopyridine (4AP) (94.1 mg, 1 mmol) was lightly ground with agate pestle and mortar. During grinding, two drops of ethanol were added, and the mixture was ground until the powder was dry. The solvent was added repeatedly for 30 min. For diffusion, a powdered mixture of GLI (161.7 mg, 0.5 mmol) and 4AP (47.0 mg, 0.5 mmol) was dissolved in 5 mL of ethanol. The remaining insoluble powder was removed by filtration. The vial containing ethanol solution was transferred to a larger vial containing diethylether solvent. The larger vial was then closely packed until a needle-shaped single crystal appeared from the solution within one week. 2.3 Synthesis of Gliclazide–3,4-diaminopyridine salt The 3,4-diaminopyridine (34AP) salt was prepared by the same method as the GLI-4AP salt. Very small needle-shaped single crystals were obtained after two weeks. 2.4 Powder X-ray diffraction (PXRD) PXRD measurements were performed using a SMART LAB X-ray diffractometer (Rigaku, Japan). The sample was placed between Mylar films. Powder patterns were collected from 2θ = 3°–40° in 0.01° steps at 25°C with scan speed of 3°/min (Cu-Kα source, 45 kV, 200 mA). 2.5 Single-crystal X-ray diffraction and refinements Single-crystal X-ray diffraction data for GLI-4AP were collected at 223(2) K in the ω-scan mode with R-AXIS RAPID II (Rigaku, Japan) using Cu-Kα X-rays obtained from a rotating anode source with focused mirror optics (λ = 1.541865



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Å). Because GLI-34AP crystals were extremely thin (0.40 × 0.10 × 0.01 mm), single-crystal X-ray diffraction measurements were conducted at the SPring-8 synchrotron facility, Hyogo Prefecture, Japan. Data were collected on a large cylindrical IP/CCD camera in the BL02B1 beamline using a MERCURY II CCD Camera (Rigaku, Japan). The synchrotron radiation was monochromated using a Si(311) double-crystal monochromator (λ = 0.700400 Å). Measurements were performed at 173(2) K. Integrated and scaled data were empirically corrected for absorption effects using ABSCOR.27 The initial structure was solved by using the direct method with SHELXS 97 and refined on F02 with SHELXL 97.28 All non-hydrogen atoms were refined anisotropically. The hydrogen atoms attached to nitrogen atoms were located from the difference Fourier map and were refined isotropically. All other hydrogen atoms were located geometrically and treated by a riding-atom model. 2.6 Computational method A thermal ellipsoid drawing and hydrogen bond analysis were generated from PLATON.29 The co-former occupied space was calculated using MERCURY 3.6 software30 by the contact surface method with probe radius and approximate grid spacing of 1.2 and 0.7 Å, respectively. The theoretical molecular volume was calculated using VEGA ZZ 3.1.0.31 2.7 Dissolution rate measurement The dissolution rates of pure GLI, GLI-4AP, and GLI-34AP in powder form were studied using the US pharmacopoeia tablet dissolution test apparatus-2 (Miyamoto Riken, Japan) at paddle rotation speed of 50 rpm in 900 mL of 0.1 N


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HCl containing 0.25% (w/v) of sodium lauryl sulfate as a dissolution medium at 37.5 ± 0.5°C.7 The powder equivalent to 100 mg of GLI was weighed and added to the dissolution medium. At specified times (every 10 min for 90 min), 10-mL samples were withdrawn by using syringe and filtered with ethyl cellulose 0.45-µm filter (Advantec, Japan). The GLI content in GLI, GLI-4AP, and GLI-34AP was measured at 227, 228, and 228 nm, respectively, using a UV-Visible spectrophotometer (Jasco V560, Japan). A fresh medium that was prewarmed at 37°C was added to maintain constant volume. Dissolution rates were determined in triplicate. 2.8 Differential scanning calorimetry (DSC) DSC measurements were performed using DSC 8230L (Rigaku, Japan). Around 2–3 mg of the sample was accurately weighted and placed in an aluminum pan that was then closed. The sample was heated at a rate of 3°C/min from 20 to 200°C under nitrogen purge of 100 mL/min; an empty closed aluminum pan was used as a reference. 3. Results and discussions Targeting the occurrence of isostructurality, a series of salt-forming (base) co-formers were investigated experimentally. Among them, 4-aminopyridine (4AP) and 3,4-diaminopyridine (34AP) formed isostructural crystals. Powder crystals of these salts were obtained by co-grinding, and the powder diffraction patterns and simulated patterns of the crystal structures of GLI-4AP and GLI-34AP were the same, indicating that pure phases were obtained by grinding (Figure 1).



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Figure 1. Comparison of powder patterns and simulated patterns of GLI salts from their respective structures.

Table 1 shows the crystallographic data. Both crystals were crystallized in a monoclinic system with the same space group P21/c. The unit cell similarity index (П) and mean elongation (ε) values were calculated.32 П and ε for GLI-4AP/GLI-34AP salt were 0.001 and 0.014, respectively. These values support the isostructurality of the two crystals. Figure 2 shows a thermal ellipsoid drawing of the two salts in asymmetric units. When GLI forms a multicomponent crystal with 4AP and 34AP, either a salt or a co-crystal can be formed. In a difference Fourier map, significant residual density was observed near the pyridine ring in both 4AP and 34AP molecules, which was suitable for the N-H hydrogen atom. Thus, it was assigned as a transferred hydrogen atom. In addition, no significant residual density peak is observed for the N atom of the sulphonyl urea in the GLI molecule, indicating that the hydrogen atom is transferred to the pyridine ring of 4AP and 34AP. Furthermore, the ∆pKa values of this multicomponent crystal are large enough,


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being 7.80 for 4AP and 7.71 for 34AP.33 Thus, these data clearly indicate salt formation in the multicomponent crystals.

Figure 2. Thermal ellipsoid drawing of (a) GLI-4AP and (b) GLI-34AP at 50% probability level. The dashed lines in the GLI-4AP structure indicate the minor disordered parts. Table 1. Crystallographic details of GLI-4AP and GLI-34AP Parameter

GLI-4AP

GLI-34AP

Crystal system

Monoclinic

Monoclinic

Space group

P21/c

P21/c

a (Å)

13.2047(3)

13.0925(10)

b (Å)

8.6431(2)

8.9559(7)

c (Å)

19.7492(4)

19.4796

β (°)

112.3910(10)

107.547(8)

V (Å3)

2084.03(8)

2177.8(3)

Z,Z’

4,1

4,1

T (K)

223(2)

173(2)

Measured ref.

23309

13847



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Independent ref.

3799 (Rint = 0.0511)

4984 (Rint = 0.0511)

Refined parameters

294

372

Goodness-of-fit on F2

1.087

1.027

Final R indices [I>2σ(I)]

R1 = 0.0455

R1 = 0.0441

GLI-4AP showed a disordered structure both in the drug (GLI) and in the co-former (4AP) molecules. The terminal five-membered ring of GLI existed in two alternative open envelope conformations in a 61:39 ratio. The 4AP molecules were oriented in two opposite directions on the common plane in an 80:20 ratio. This type of disorder is often seen in disordered toluene solvate crystals. Figure 3 shows packing drawings viewed along the b-axis, in which co-former molecules of 4AP and 34AP are removed; the remaining voids (co-former occupied spaces) are shown as a golden cloud in Figure 3c and d. Figure 3a and b confirm that GLI-4AP and GLI-34AP are isostructural, respectively. The co-former occupied spaces are slightly different in the two crystals. The co-former occupied spaces in 4AP and 34AP salts in one unit cell are 444.56 and 463.52 Å3, respectively. As expected, the large co-former occupied space in the 34AP salts corresponds to the addition of one amino moiety. Furthermore, the volume for 4AP is large enough compared to the theoretical volume of 4AP (87.3 Å3), which allows the 4AP molecule to show a disordered structure. Interestingly, the packing efficiency of 4AP and 34AP salts is 67.0% and 67.9%, respectively. Notwithstanding the fact that measurements


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are performed at different temperatures, these data indicate that the 34AP salt has slightly better and more efficient packing.

Figure 3. Packing view of (a,c) GLI-4AP and (b,d) GLI-34AP along b-axis. Co-former molecules are drawn in space filling setting in (a) and (b) and omitted in (c) and (d). Co-former occupied spaces are indicated by yellow translucent spheres in (c) and (d). Minor components of the disordered structure are omitted for clarity.

In this simple manner, isostructurality can be achieved reliably using a recurring structural basis unit with the same or similar hydrogen bond.34 To realize similar hydrogen bonds, using different co-formers with similar shape, size, or complementary functional group is an effective approach. In this study, robust one-dimensional (1D) chains comprising GLI molecules were observed,



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in which two chains connected by intermolecular interactions involving co-former molecules were crucial to isostructurality. In both crystal structures, GLI molecules form a 1D chain structure around the crystallographic 21 screw axis along the b-axis using N2-HYO2 hydrogen bonds (Figure 4a and b). Counter-ions exist between the chain structures of GLI molecules and connect them around the center of symmetry using hydrogen bonds (Figure 4c and d). In this crystal structure, one layer of GLI and co-former molecules connected by hydrogen bonding in the ac plane (Figure 4c and d) is observed; this is hereafter defined as a two dimensional (2D) sheet.

Figure 4. 1D chain structure of (a) GLI-4AP and (b) GLI-34AP. Each 1D chain is connected to another chain to form a 2D sheet structure of (c) GLI-4AP and (d) GLI-34AP via intermolecular interaction involving co-former molecules. Hydrogen atoms and a minor part of GLI-4AP are omitted for clarity. GLI and co-former molecules are indicated by capped sticks and a wireframe setting, respectively. Yellow circles in (c) and (d) indicate inversion centers.


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A detailed view of the interaction between GLI and the co-former reveals an interesting feature, namely, that both structures form a dimeric structure around the inversion center. It should be noted that both major and minor parts are involved in the intermolecular interaction to form a dimeric structure in GLI-4AP. Moreover, the minor part of GLI-4AP shares a similar hydrogen bond pattern with GLI-34AP. Therefore, it is necessary to include the 20% minor part of GLI-4AP to explain the isostructurality in this present work. Table 2 shows the details of the hydrogen bonds in these crystals. Table 2. Selected hydrogen bonds in GLI-4AP and GLI-34AP GLI-4AP D-H,A

d (H,A)/ Å

d (D,A)/ Å

∠(D-H...A)/°

N2-H...O21

2.27(2)

3.091(2)

165.6(2)

N4A+-HYN12*

2.09

2.948(2)

166.8

N4A+-HYO12*

2.54

3.073(2)

120.1

N5A-HYO13*

2.16

2.947(3)

149.9

N5A-H...N3-1*

2.08

2.938(2)

166.6

C20A-HYO34*

2.28

3.190(3)

162.8

N5B-HYO34**

2.17

2.963(9)

151.4

N5B-HYN13**

2.10

2.931(10)

159.0

C20B-HYO13**

2.17

3.022(10)

151.0

N4B+-HYN3-4**

2.13

2.949(10)

156.1

1

-x, y-1/2, -z+1/2;2 -x,-y+1,-z+1;3x,y-1,z;4x,-y+1/2,z+1/2

*hydrogen bond between GLI and major part of 4AP; **hydrogen bond between GLI and minor part of 4AP GLI-34AP D-H,A

d (H,A)/ Å

d (D,A)/ Å

∠(D-H...A)/°

N2-H...O21

2.20(2)

3.050(2)

171.0(2)



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N6-HYO32

2.09(3)

2.939(2)

169.0(2)

N4+-HYN3-

2.00(2)

2.848(2)

163.0(2)

N5-HYO14

2.12(3)

3.014(2)

176(2)

C20-HYO11

2.40(2)

3.235(2)

154.8(2)

N6-HYN13

2.09(3)

2.939(2)

169.0(2)

3.225(2)

146.0(2)

N5-HYO13 1

2.60(3) 2

3

4

-x+1,y-1/2,-z+1/2; -x+1,-y+1,-z; x,-y3/2,z-1/2; -x+1,y+1/2,-z+1/2

Figure 5. Similar centrosymmetric dimer of GLI-4AP ((a) major and (b) minor part) and (c) GLI-34AP. Hydrogen bonds are indicated by dashed-blue lines.

The major and minor parts in 4AP have a different hydrogen bond type to retain the centrosymmetric dimer. As shown in Figure 5a and b, two exchanging


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hydrogen bond donors (N4A+ ↔ N5B and N5A ↔ C20B + N4B+) were observed as a result of positional disorder. Owing to the preservation of the similar dimeric structure, different hydrogen bond features are also observed in GLI-34AP (Figure 5c). Interestingly, the minor component of GLI-4AP is more similar to GLI-34AP than the major component. In the major part of GLI-4AP, a N atom of the pyridine ring forms a bifurcated hydrogen bond N4A-HYN1 and N4AYO1. On the other hand, a N atom of the amino moiety in aminopyridine also forms a bifurcated hydrogen bond N5A-HYO1

and

N5A-HYN3.

An

unconventional

hydrogen

bond

of

C20A-HYO3 is also observed; this bond stabilizes the dimeric structure. In the minor part, a N atom of the pyridine ring only forms one charge-assisted hydrogen bond N4B+-HYN3-. The bifurcated hydrogen bonds N5B-HYN1 and N5B-HYO1 are observed to connect the amino moieties of 4AP with GLI molecules. An unconventional hydrogen bond involving C20 is also observed in the minor part; this bond stabilizes the dimeric structure. A more complicated hydrogen bond architecture is observed in GLI-34AP. The N atom in the pyridine ring forms a charge-assisted hydrogen bond N4+-HYN3-. The first amino moiety (N5) forms two hydrogen bonds to the same atom O1 via different two symmetric operations x,

-y3/2,

z-1/2 and -x+1,

y+1/2, -z+1/2. Another amino moiety interacts with two GLI molecules and forms bifurcated hydrogen bonds N6-HYO3 and N6-HYN1. One unconventional hydrogen bond C20-HYO1 is observed to stabilize the dimeric structure in GLI-34AP.



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Even if the molecular arrangements in the lattice are equally matched, it is not fully guaranteed that the physicochemical properties are same or similar.34 Considering the fact that the GLI raw materials are classified as BCS class II,7 we investigate the in vitro dissolution profile. It is well known that for BCS class II drugs, the rate of dissolution in the gastrointestinal tract becomes the rate-limiting step from the viewpoint of bioavailability. During in vitro dissolution tests, 0.25% (w/v) of sodium lauryl sulfate was added to reduce the effect of wettability. Salt formation has attracted much interest owing to the better solubility or dissolution corresponding to its free acid or base. Moreover, dissolution upon salt formation is usually higher than that of co-crystals. The conventional mechanism proposed for the remarkable improvement in dissolution is that the cationic and anionic forms of the molecule have better affinity to water compared to the neutral species.35 In this study, we found that isostructural salts show enhanced dissolution rate relative to their raw material, although the dissolution profile between the salts is slightly different by means the dissolution rate of GLI-4AP is faster than GLI-34AP (Figure 6).

Figure 6. Dissolution profiles of GLI (green), GLI-4AP (blue), and GLI-34AP (red).


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Between these binary systems, GLI-4AP shows the maximum dissolution in 20 min, whereas GLI-34AP needs additional time to reach the same level of dissolution. The solubility of a multicomponent crystal can be affected by various factors such as packing efficiency and energetical aspects. In this study, these two approaches are used to rationalize the differences in the dissolution profiles. As mentioned above, GLI-4AP has slightly lower packing efficiency compared to its counterpart. Therefore, it is expected that the 4AP salt has higher dissolution rate. The second approach is the energetical difference between two crystals. The lattice energy is known to be correlated with the solubility and dissolution of a compound. Moreover, the lattice energy qualitatively correlates with the melting point of a solid system. As shown in Fig. 7, GLI-4AP and GLI-34AP have onset melting points of 141.6 and 151.7°C, respectively. Notwithstanding the different molecular entities, the lower melting point of 4AP salt indicates lower lattice energy that in turn leads to faster dissolution.

Figure 7. DSC scans of GLI-4AP (blue) and GLI-34AP (red).



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By performing DSC measurements, we can also observe the tendency of the solid behavior during heating. The absence of any thermal moment prior to the melting point indicates that no polymorphism was observed from the bulk powder of 4AP and 34AP salts. Both salts show the same characteristic after melting owing to the occurrence of decomposition. It is generally known that an ionic salt usually disintegrates upon melting.

4. Conclusions

Isostructural salts of GLI were synthesized using 4-aminopyridine and 3,4-diaminopyridine as co-formers. A robust 1D hydrogen bond chain of the GLI molecule and centrosymmetric dimer structure formed between GLI and the co-former. Although salts tend to have higher dissolution rates compared to their raw material, the dissolution rate of isostructural salts did not show a similar trend. Considering its weaker intermolecular interaction and lower melting point, 4-aminopyridine salt had higher dissolution rate. Our study suggests that an isostructural salt could be explored as an alternative solid form to improve the dissolution rate of drugs. This study also shows that the properties could be different although the structure is equally matched.

Associated contents

Supporting information


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The Supporting Information is available free of charge on the ACS Publications website at DOI: xxx

Accession Codes

CCDC 1446051 and 1446053 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by e-mailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Author Information

Corresponding author

*E-mail: [email protected]

Notes

The authors declare no competing financial interest.

Acknowledgements O. D. P wishes to thank MEXT for the research fellowships. Synchrotron radiation experiments were performed at the BL02BI beamline of Spring-8 with the approval of the Japan Synchrotron Radiation Research Institute



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(JASRI, Proposal No. 2014B1004). We acknowledge Dr. Kohei Johmoto for the measurements of the single crystal at the synchrotron facility.

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For Table of Contents Use Only

Isostructural Multicomponent Gliclazide Crystals with Improved Solubility Okky Dwichandra Putra,a Etsuo Yonemochi,b and Hidehiro Uekusaa* a

Department of Chemistry and Materials Science, Tokyo Institute of Technology,

Ookayama 2-12-1, Meguro-ku, Tokyo 152-8551, Japan b

School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41,

Ebara, Shinagawa, Tokyo 142-8501, Japan

Synopsis Gliclazide, a drug used for treating diabetes mellitus, formed an isostructural salt with aminopyridine derivatives. These salts showed a promisingly higher dissolution rate relative to their raw materials.


Isostructural Multicomponent Gliclazide Crystals with Improved

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