A new polymorph and two pseudopolymorphs of pyrimethamine

Tutughamiarso, Maya; Bolte, Michael

doi:10.1107/s0108270111038868

Cited by 9 publications

(10 citation statements)

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“…Its protonation state and the relative orientation of the pyramidine and arene rings is important for understanding the mode of action of the compound under study (Sansom et al, 1989;Kongsaeree et al, 2005). The crystal structures of a solvent-free polymorph of pyrimethamine and two pseudopolymorphs have been studied and contained cyclic hydrogen-bonded motifs self-organized in different ways to produce new hydrogen-bonding motifs and supramolecular patterns (Tutughamiarso & Bolte, 2011). In this study, we report the cocrystal structure of 2,4-diamino-5-(4chlorophenyl)-6-ethylpyrimidin-1-ium 2,4-dihydroxybenzoate methanol monosolvate, (I), and an estimation of its electrostatic properties using a transferred multipolar atom model from the ELMAM2 database.…”

Section: Introductionmentioning

confidence: 99%

Electrostatic properties of the pyrimethamine–2,4-dihydroxybenzoic acid cocrystal in methanol studied using transferred electron-density parameters

et al. 2018

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The crystal structure of the cocrystal salt form of the antimalarial drug pyrimethamine with 2,4-dihydroxybenzoic acid in methanol [systematic name: 2,4-diamino-5-(4-chlorophenyl)-6-ethylpyrimidin-1-ium 2,4-dihydroxybenzoate methanol monosolvate, CHClN·CHO·CHOH] has been studied using X-ray diffraction data collected at room temperature. The crystal structure was refined using the classical Independent Atom Model (IAM) and the Multipolar Atom Model by transferring electron-density parameters from the ELMAM2 database. The Cl atom was refined anharmonically. The results of both refinement methods have been compared. The intermolecular interactions have been characterized on the basis of Hirshfeld surface analysis and topological analysis using Bader's theory of Atoms in Molecules. The results show that the molecular assembly is built primarily on the basis of charge transfer between 2,4-dihydroxybenzoic acid and pyrimethamine, which results in strong intermolecular hydrogen bonds. This fact is further validated by the calculation of the electrostatic potential based on transferred electron-density parameters.

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Section: Introductionmentioning

confidence: 99%

Electrostatic properties of the pyrimethamine–2,4-dihydroxybenzoic acid cocrystal in methanol studied using transferred electron-density parameters

et al. 2018

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“…We emphasise that our findings resulted from the specific recrystallization technique described in this paper. Figure 2 depicts the XRPD pattern of Pyr-MeOH in comparison with one of the known anhydrous forms of pyrimethamine (Pyr) (6,22). Anhydrous pyrimethamine herein referred to as Pyr references to anhydrous pyrimethamine described by Sethuraman and Muthiah (22), whereas Pyr 2 refers to anhydrous pyrimethamine described by Tutughamiarso and Bolte (6).…”

Section: Identification and Classification Of The Recrystallization Pmentioning

confidence: 99%

“…Single crystal XRD yielded the unit cell parameters of Pyr-MeOH (Table 1) ). Furthermore, only one molecule of the API in the asymmetric unit of Pyr-MeOH has a principal torsion angle value (-104.7(2)) equal to that of a molecule in the asymmetric unit of unsolvated Pyr; instead, for the other pair of molecules, the corresponding torsion angles are -75.1(2) in PyrMeOH and -81.2(1) in unsolvated Pyr (6).…”

Section: Structure Elucidationmentioning

confidence: 99%

“…Pyrimethamine ( Figure 1) has been used in the treatment of uncomplicated malaria for more than 30 years (3,4). Different solid forms of pyrimethamine have been described as early as 1976 (5), and yet the discovery of new solid forms in 2011 and 2012 (6,7) revealed that its solid state chemistry has still not yet been exhaustively elucidated.…”

Section: Introductionmentioning

confidence: 99%

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The Risk of Recrystallization: Changes to the Toxicity and Morphology of Pyrimethamine

2014

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-PURPOSE. Pyrimethamine, an anti-malarial agent known to exhibit solid state polymorphism, may be purified by means of recrystallization. Recrystallization may alter the solid state chemistry of pharmaceuticals, which may impact the toxicity and/or manufacturability thereof. We evaluated the risks associated with the recrystallization of pyrimethamine. METHODS. Pyrimethamine was recrystallized using several organic solvents. X-ray diffraction, thermal analysis, infra-red spectroscopy, microscopy, flowability -, solubility and dissolution testing as well as computational work were employed to evaluate the recrystallized products. RESULTS. A toxic solvatomorph of pyrimethamine (Pyr-MeOH) was found to be the product from methanol recrystallization. The elucidation of -and the elaboration on the unique characteristics of Pyr-MeOH provides the pharmaceutical industry with several means to identify Pyr-MeOH and to distinguish it from the pharmaceutically preferred anhydrous form (Pyr). Thermal methods of analysis found that the toxicity of PyrMeOH may be reversed by overcoming a desolvation activation energy of 148 kJ/mol. In addition it was found that recrystallization altered the morphology of Pyr. Angle of repose and tapped density determinations identified that the different morphologies of Pyr displayed differences in powder flow and compressibility behaviour and In Silico calculations were successful in rendering morphologies resembling that found experimentally. CONCLUSION. We present a solvatomorph of pyrimethamine and provide several characteristic means to identify this unwanted toxic form and quantified the energy required to overcome its toxicity. In addition we describe that Pyr may present in different morphologies and show how it may impact the manufacturability thereof.

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“…During cocrystallization the p K a values of the reactants play a significant role in the formation of a salt or cocrystaldepending on the Δp K a (i.e., difference in p K a of the most basic site of the base and most acidic site of the acid) either salt or cocrystal may be formed. − Cocrystal formation is expected for Δp K a < 0 and that of a salt for Δp K a > 3, while for a Δp K a value in the range 0–3 both forms as well as a product with partial proton transfer may be obtained − This motif has been also observed for many pyrimethamine salts and cocrystals. Usually, in the design of new forms of pyrimethamine, a supramolecular synthon appearing in its binding with DHFR, based on N–H···O hydrogen bonds between the protonated aminopyrimidine group of PYR and the carboxylate group, is used.…”

Section: Introductionmentioning

confidence: 99%

Influence of Hydroxyl Group Position and Substitution Pattern of Hydroxybenzoic Acid on the Formation of Molecular Salts with the Antifolate Pyrimethamine

Ceborska

Kędra-Królik

Narodowiec

et al. 2021

Crystal Growth & Design

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A series of molecular salts of the antimalarial drug pyrimethamine (PYR) with salicylic acid (SA) and its methyl-substituted derivatives 3-methylsalicylic acid (3Me-SA), 4-methylsalicylic acid (4Me-SA), and 5-methylsalicylic acid (5Me-SA) was obtained. Additionally, cocrystallization of PYR with the structural analogues of SA 3-hydroxybenzoic acid (3OH-BA) and 4-hydroxybenzoic acid (4OH-BA) led in the case of 3OH-BA to the formation of a molecular salt, while cocrystallization with 4OH-BA did not lead to the formation of an associate of any kind. In all obtained crystal structures, the carboxylate anion interacts with the protonated at N1 pyrimethamine moiety in a linear fashion through a pair of parallel N–H···O hydrogen bonds forming a cyclic hydrogen-bonded motif. In the crystal structure of PYR-SA as well as in the structures involving methylated derivatives of SA (3Me-SA, 4Me-SA, and 5-Me-SA), a typical PYR-PYR association via a pair of N–H···N bonds between the N(4)H2 amino group of one molecule and the N3 unsubstituted amino atom of the second PYR molecule is observed, a motif that is characteristic of two known PYR polymorphs. On the other hand, in the structure of PYR-3OH-BA, the PYR-PYR connection is realized via a pair of N–H···N bonds between the N(2)H2 amino group of one molecule and the N3 unsubstituted amino atom of the second PYR molecule. In all of the structures, chlorine atoms are involved in C–H···Cl interactions with either the acid molecule or another PYR moiety, while in the structure of PYR-3Me-SA molecules are additionally connected through halogen Cl···Cl interactions. All of the obtained structures were thoroughly characterized by single-crystal X-ray analyses, Hirshfeld analyses, DFT calculations, and thermal analyses (TGA and DSC).

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A new polymorph and two pseudopolymorphs of pyrimethamine

Cited by 9 publications

References 29 publications

Electrostatic properties of the pyrimethamine–2,4-dihydroxybenzoic acid cocrystal in methanol studied using transferred electron-density parameters

Electrostatic properties of the pyrimethamine–2,4-dihydroxybenzoic acid cocrystal in methanol studied using transferred electron-density parameters

The Risk of Recrystallization: Changes to the Toxicity and Morphology of Pyrimethamine

Influence of Hydroxyl Group Position and Substitution Pattern of Hydroxybenzoic Acid on the Formation of Molecular Salts with the Antifolate Pyrimethamine

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