Anion exchange reaction for preparing acesulfame solid forms

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Anion exchange reaction for preparing acesulfame solid forms Chenguang Wang, Sathyanarayana Reddy Perumalla, and Changquan Calvin Sun Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00106 • Publication Date (Web): 28 Jun 2018 Downloaded from http://pubs.acs.org on June 29, 2018

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Crystal Growth & Design

Anion exchange reaction for preparing acesulfame solid forms

Chenguang Wang #, Sathyanarayana Reddy Perumalla #, and Changquan Calvin Sun *

Pharmaceutical Materials Science and Engineering Laboratory, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA

# C.G.W. and S.R.P. contributed equally to this work.

*Corresponding author Changquan Calvin Sun, Ph.D. 9-127B Weaver-Densford Hall 308 Harvard Street S.E. Minneapolis, MN 55455 Email: [email protected] Tel: 612-624-3722 Fax: 612-626-2125

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Abstract Improving taste and tuning physicochemical properties of active pharmaceutical ingredients (API) by forming new salts or cocrystals with an artificial sweetener, such as saccharine (Sac) and acesulfame (Acs), is an effective crystal engineering strategy for facilitating successful delivery of bitter drugs. However, the number of reported solid forms of Acs is curiously lower (29) than that of Sac (275). An analysis of the literature revealed that the preparation of salts or cocrystals of Acs was hindered by the difficulty and cost in preparing Acs free acid from commercially available potassium salt (Acs-K). Here, we evaluated the broad applicability of an anion exchange reaction for preparing Acs solid forms using nine model compounds. In all cases, we successfully prepared Acs crystals, based on single crystal structure determination, simply from ion exchange between Acs-K and corresponding salts. The proton transfer propensity, hydrogen-bonding pattern, amide group keto–enol tautomerism in the Acs crystals are also discussed.


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The crystallization of molecular complexes to form new solid forms, such as salt and cocrystal, is a long standing strategy for engineering active pharmaceutical ingredients (API) to overcome deficient pharmaceutical properties, such as poor solubility, phase stability, and tabletability.1-3 A unique class of such crystals consists of salts or cocrystals of APIs with potent artificial sweeteners, such as saccharin (Sac) and acesulfame (Acs) (Figure 1),2, 4-6 Such sweet solid forms are effective in solving the problem of offensive taste of APIs, in addition to the potential improvement in other common pharmaceutical properties brought about by crystal structure modifications. Advantages in using Sac and Acs include: 1) they are safe for human consumption, which is essential for gaining approval by US Food and Drug Administration to use such new solid forms in drug products without requiring extensive toxicological and clinical trials to establish their safety profiles; 2) as non-nutritive high-intensity sweeteners, they offered ≥200 fold sweetness intensity than sucrose7,

8

and the ability to effectively mask offensive taste of APIs for easier

formulation development;4, 9-13 3) their amide and sulfonyl amide functional groups are effective heterosynthon for salt or cocrystal formation (Figure 1);14, 15 4) their strong acidity (pKa = 1.6 and 2.0 for Sac and Acs, respectively) facilitates interactions with a wide range of basic molecules; 5) their much lower molecular weights (183.2 and 163.2 g/mol for Sac and Acs, respectively) than other artificial sweeteners, e.g., aspartame (294.3 g/mol), sucralose (397.4 g/mol), neotame (378.4 g/mol), advantame (458.5 g/mol), steviol glycosides (318.5 g/mol), favor the delivery of more API in a unit weight, which gives more formulation space for tablet design. Sweet salts and cocrystals of a number of APIs, such as quinine, norfloxacin, ciprofloxacin, berberine, griseofulvin, haloperidol, theophylline, stanozolol, salinazid, and fluorocytosine, have been reported.4, 12, 16-19 A curious observation is that Acs has been far less frequently used than Sac to prepare sweet crystals, despite the structural resemblance between them, i.e., presence of the amide and sulfonyl amide functional groups.

A search of the Cambridge Structural Database 3

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returned 275 records for crystals containing Sac (225 in ionic form, 36 in neutral form, and 14 in both ionic and neutral forms, Table S1), while only 29 for Acs (25 ionic and 4 neutral forms, Table S2).20

a)

b)

c)

Figure 1. Molecular structures of a) saccharin keto tautomer, b) acesulfame keto tautomer, and c) acesulfame enol tautomer.

Upon reviewing the literature pertaining to the crystallization of Acs containing solids, one common theme emerged, i.e., Acs free acid was invariably used for preparing salts or cocrystals. Since Acs is not commercially available, it was prepared from commercially available potassium salt, Acs-K, using a relatively laborious process that involves 1) neutralization by HCl in an aqueous solution, 2) extraction of Acs using ethyl acetate, and 3) drying.

21

Acs free acid thus

prepared was then used to prepare the Acs salts or cocrystals through solvent evaporation, slurry, or grinding approaches. 4-8, 11, 12 This laborious procedure certainly discouraged the use of Acs to prepare sweet crystals. The commercial unavailability of Acs may be attributed to its softness, low melting point, poor chemical stability, and polymorphism.

21

In fact, the crystal structure of Acs

free acid was not solved until 2010. The ~120°C melting point of Acs is much lower than that of Acs-K (>210 °C).

21

In comparison, Sac is are commercially available, which correspond to

excellent thermal stability (physically stable up to ~230 °C).6, 22

Therefore, it is practically much

easier to prepare new sweet crystals using Sac than using Acs.


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An alternative method for preparing Acs complexes is the anion exchange, or salt metathesis, reaction, where Acs-K and a salt of basic API are suspended in an appropriate solvent to form phase pure Acs-API crystals (Scheme 1). This method is expected to generate the Acs-API complex provided solubility of the complex is lower than ACS-K and the starting API salt. The Acs-API complex can be a salt or cocrystal, depending on whether or not a proton has transferred from Acs to API in the crystal. Considering the fact that approximately half of marketed drugs are salts and the commercial availability of Acs-K, the ion exchange reaction can be easily adopted to prepare new solids with Acs. We previously used this reaction to successfully prepare Acs salts with berberine, metformin, and diphenhydramine.9-11, 23 However, the broad applicability of this method in preparing new solid forms with Acs has not been systematically demonstrated. In this communication, we have tested the applicability of the anion exchange reaction in preparing AcsAPI solid forms using eight bitter model APIs, i.e., hydrochloride salts of nicotinamide (NIC), niacin (NIA), lamivudine (LMV), norfloxacin (NOR), ciprofloxacin (CIP), caffeine (CAF), 5fluorocytosine (FC), and sildenafil citrate (SIL) (Figure 2). The nucleobase, cytosine (CYT), is also included since FC is a derivative of CYT and both of them are known to form conjugate acid base (CAB) cocrystal.

a

+

+ b

+

Scheme 1. Schematic representation of the anion exchange reaction to prepare new solid form. a) acesulfame cocrystal, and b) acesulfame salt. 5 ACS Paragon Plus Environment


a)

f)

b)

g)

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d)

c)

h)

e)

i)

Figure 2. Molecular structure of a) cytosine, b) fluorocytosine, c) nicotinamide, d) niacin, e) caffeine, f) lamivudine, g) norfloxacin, h) ciprofloxacin, i) sildenafil.

NIC is used in over-the-counter drugs for pellagra and acne. It is a GRAS compound that has been frequently used as a cocrystal former during solid form screening. NIA is used in medications for treating high blood cholesterol and pellagra. The molecular structure of NIA is different from NIC onlyat the 3-position of the pyridine ring (carboxyl group in NIA and carboxamide group in NIC). LMV is used in antiretroviral medications to treat HIV/AIDS. NOR and CIP are commonly used high dose fluoroquinolone antibacterial drugs. CAF is a xanthine alkaloid with multiple medical uses and is also a GRAS compound. SIL is used for treating male erectile dysfunction and FC is an antifungal medication.

Additional, NIC, LMV, FC, CIP

hydrochloride, and CAF citrate salt are in the list of essential medicines by World Health Organization. Among them, Acs crystals with 3 APIs were prepared using solution crystallization methods,16, 19 but no Acs crystals with the other 6 compounds were reported. Most of the reactions were carried out by dissolving equi-molar of Acs-K and corresponding API salt in water at room temperature (Table 1). However, the reactions for FC and CYT were set up using equi-molar of each compound along with respective hydrochloride salt and Acs-K because 6 ACS Paragon Plus Environment

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CAB cocrystal was known for FC 19 and suspected for CYT.24 Acs-SIL single crystals suitable for structure determination were grown from ethanol to obtain an anhydrate and acetonitrile (ACN) to obtain an acetonitrile solvate. Single crystals of all other Acs-API were grown from water. In all cases, single crystals were obtained by slow evaporation at room temperature (See details in SI). Acs crystal with all 9 model compounds were successfully obtained using the anion exchange reaction for a total of ten crystal forms (Table 1). Unit cell parameters of the three known Acs-API crystals matched with the corresponding known crystal structures. Structures of the seven new Acs-API crystals are shown in Figure 3 (structure descriptions are provided in SI), with crystallographic parameters given in Tables S3-S9 and asymmetric units shown in Figure S1. It was claimed that the CAF could form unionized molecular complexes with Acs in 1:1 or 1:2 molar ratios.25 This claim is confirmed in this work because both the PXRD of the bulk powder and that calculated from the solved structure of the cocrystal conform to that of the previously reported 1:2 complex. Table 1. Summary the solid form screen results using the anion exchange reaction with Acs-K. Starting salt

Stoichiometry of Acs-API crystal

Solvent

pKa of APIa

Comment

Nicotinamide HCl

1-1

water

3.35

Salt hydrate

Niacin HCl

1-1

Water

4.75

Salt

Lamivudine HCl

1-1

Water

2.382

Salt

Sildenafil citrate

1-1

Ethanol

5.99

Salt (anhydrate)

Sildenafil citrate

1-1

Acetonitrile

5.99

Salt (solvate)

Norfloxacin HCl

1-1

Water

6.34, 8.75

Salt16

Ciprofloxacin HCl

1-1

Water

6.09, 8.73

Salt16

Caffeine HCl

1-2

Water

3.626

Cocrystal

Cytosine HCl

2-1

Water

4.45

CAB cocrystal

Fluorocytosine HCl

2-1

Water

3.26

CAB cocrystal19



a.

from PubChem.

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Figure 3. Packing patterns of the seven new crystal forms of Acs. a) Acs-NIC salt monohydrate, b) Acs-NIA salt, c) Acs-LMV salt, d) Acs-SIL acetonitrile solvate, e) Acs-SIL salt, f) Acs-CAF cocrystal, g) Acs-CYT CAB cocrystal.

The availability of a total of 36 Acs containing crystal structures (29 reported and 7 determined in this work), make it an acceptable size of data set to analyze proton transfer propensity, hydrogen bonding pattern and keto-enol tautomerism of Acs. Acs adopts the keto form in all 31 Acs salts and 2 free acid, the enol form in Acs-griseofulvin and Acs-CAF cocrystals, and both tautomers in Acs-theophylline cocrystal.12 The hydrogen bond accepting ability of C=O was suggested to be higher than S=O in Acs keto forms,15 which is consistent with the more negative charge distribution of C=O (-127 kJ/mol) than S=O (-97 kJ/mol, see Figure 4a, the electrostatic potential map28). In contrast, although only confirmed by the 3 known crystal structures, the minimum electrostatic potential (Emin) of S=O suggests it is the preferred hydrogen bond acceptor in 8 ACS Paragon Plus Environment

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the enol form (Figure 4b). The maximum electrostatic potential (Emax) corresponds to the -NH group in the keto form and -OH group in the enol form (Figure 4), suggesting their strongest hydrogen donating ability in respective tautomers. A significantly higher positive charge of -NH (223 kJ/mol) in the keto form than -OH (192 kJ/mol) in the enol form suggests that the keto form can donate proton more readily than the enol form. This explained why the keto form is observed in all known crystal structures of Acs salts.

a)

b)

Figure 4. Molecular electrostatic potentials maps of acesulfame a) keto form and b) enol form. (Calculated based on density functional B3LYP level of theory using 6-311++G**(d,p) basis set).

The conversion between Acs keto and enol forms inevitably alters the bond length between C-O and C-N in the amide group, where the double bond would correspond to shorter bond length. In addition, proton transfer is also known to change the bond lengths of the amide group (C-N and C-O bond lengths).29 These effects were examined along with the same function group in Sac, which does have a large number of salt and cocrystal forms, as a reference.30 For Sac, ionization tends to increase C-O and shorten C-N but the keto tautomer is always observed.31 Therefore, the distribution of bond length can be roughly divided into two groups according to ionization state (Figure 5). However, three groups may be identified for Acs, a) ionized keto Acs; b) neutral enol 9 ACS Paragon Plus Environment


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Acs; and c) neutral keto Acs. The ionized Acs in the 30 structures always exists in the keto form with bond length distribution that overlays with that of ionized Sac. The 3 enol form of neutral Acs are characterized with long C-O and short C-N while all 3 keto form of neutral Acs exhibit long CN and short C-O. Such bond length distribution corresponds well with the expected bond types in respective tautomers (Figure 1). The correlations among tautomerism, ionization state, and bond length of the amide group in Acs, though sensible, need to be confirmed using a much larger number of Acs structures, especially for the neutral Acs. The anion exchange method described here is expected to facilitate such an effort.

Figure 5. Bond length of C1-O1 versus C1-N1 in saccharin and acesulfame solid forms, inclusive of all unique molecular conformations in asymmetric units of crystal structures solved by single crystal X-ray diffraction only.

In summary, we have shown that the anion exchange reaction is robust for preparing new solid forms of acesulfame. This method is expected to pave the way for preparing a much larger number of acesulfame-containing crystals to not only improve pharmaceutical properties of drugs but also allow better chemical understanding of the enol-keto tautomerism in acesulfame. 10 ACS Paragon Plus Environment

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Supporting Information Materials and methods; Reference codes of crystals containing saccharin and acesulfame in Cambridge Structural Database (CSD). X-ray crystallographic parameters, hydrogen bond tables and ORTEP diagrams for the seven new acesulfame salts and cocrystals. The crystallographic data of new crystals, CCDC 1452263 – 1452269, can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Acknowledgment We thank the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for providing resources that contributed to the research results reported in this paper.

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For Table of Contents Use Only Manuscript Title: Anion exchange reaction for preparing acesulfame solid forms Authors: Chenguang Wang, Sathyanarayana Reddy Perumalla, and Changquan Calvin Sun

Synopsis Anion exchange reaction with acesulfame potassium is a powerful strategy for expanding the solid form landscape of active pharmaceutical ingredients.


Anion exchange reaction for preparing acesulfame solid forms

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