Impact of the counterion on the solubility and physicochemical properties of salts of carboxylic acid drugs

S. E. David, P. Timmins, B. R. Conway

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Aim: Salt formation is a widely used approach to improve the physicochemical and solid state properties of an active pharmaceutical ingredient. In order to better understand the relationships between the active drug, the selected counterion and the resultant salt form, crystalline salts were formed using four different carboxylic acid drugs and a closely related series of amine counterions. Thirty-six related crystalline salts were prepared, characterized and the relationship between solubility and dissolution behaviour and other properties of the salt and the counterion studied. Methods: Salts of four model acid drugs, gemfibrozil, flurbiprofen, ibuprofen and etodolac were prepared using the counterions butylamine, hexylamine, octylamine, benzylamine, cyclohexylamine, tert-butylamine, 2-amino-2-methylpropan-1-ol, 2-amino-2-methylpropan-1,3-diol andtris(hydroxymethyl)aminomethane. Salt formation was confirmed, the salts were characterized and their corresponding solubilities determined and rationalized with respect to the counterions' properties. Results and conclusion: The properties of the salt highly dependent on the nature of the counterion and, although there is considerable variation, some general conclusion can be drawn. For the alkyl amines series, increasing chain length leads to a reduction in solubility across all the acidic drugs studied and a reduction in melting point, thus contradicting simplistic relationships between solubility and melting point. Small, compact counterions consistently produce crystalline salts with high melting point accompanied with a modest improvement in solubility and the nature of hydrogen bonding between the ions has a major impact on the solubility.

LanguageEnglish
Pages93-103
Number of pages11
JournalDrug Development and Industrial Pharmacy
Volume38
Issue number1
DOIs
Publication statusPublished - Jan 2012

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Carboxylic Acids
Solubility
Salts
Pharmaceutical Preparations
Freezing
Melting point
Crystalline materials
Amines
Cyclohexylamines
Etodolac
Butylamines
Gemfibrozil
Flurbiprofen
Ibuprofen
Hydrogen Bonding
Chain length
Hydrogen bonds
Dissolution
Ions
Acids

Cite this

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abstract = "Aim: Salt formation is a widely used approach to improve the physicochemical and solid state properties of an active pharmaceutical ingredient. In order to better understand the relationships between the active drug, the selected counterion and the resultant salt form, crystalline salts were formed using four different carboxylic acid drugs and a closely related series of amine counterions. Thirty-six related crystalline salts were prepared, characterized and the relationship between solubility and dissolution behaviour and other properties of the salt and the counterion studied. Methods: Salts of four model acid drugs, gemfibrozil, flurbiprofen, ibuprofen and etodolac were prepared using the counterions butylamine, hexylamine, octylamine, benzylamine, cyclohexylamine, tert-butylamine, 2-amino-2-methylpropan-1-ol, 2-amino-2-methylpropan-1,3-diol andtris(hydroxymethyl)aminomethane. Salt formation was confirmed, the salts were characterized and their corresponding solubilities determined and rationalized with respect to the counterions' properties. Results and conclusion: The properties of the salt highly dependent on the nature of the counterion and, although there is considerable variation, some general conclusion can be drawn. For the alkyl amines series, increasing chain length leads to a reduction in solubility across all the acidic drugs studied and a reduction in melting point, thus contradicting simplistic relationships between solubility and melting point. Small, compact counterions consistently produce crystalline salts with high melting point accompanied with a modest improvement in solubility and the nature of hydrogen bonding between the ions has a major impact on the solubility.",
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Impact of the counterion on the solubility and physicochemical properties of salts of carboxylic acid drugs. / David, S. E.; Timmins, P.; Conway, B. R.

In: Drug Development and Industrial Pharmacy, Vol. 38, No. 1, 01.2012, p. 93-103.

Research output: Contribution to journalArticle

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AU - David, S. E.

AU - Timmins, P.

AU - Conway, B. R.

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AB - Aim: Salt formation is a widely used approach to improve the physicochemical and solid state properties of an active pharmaceutical ingredient. In order to better understand the relationships between the active drug, the selected counterion and the resultant salt form, crystalline salts were formed using four different carboxylic acid drugs and a closely related series of amine counterions. Thirty-six related crystalline salts were prepared, characterized and the relationship between solubility and dissolution behaviour and other properties of the salt and the counterion studied. Methods: Salts of four model acid drugs, gemfibrozil, flurbiprofen, ibuprofen and etodolac were prepared using the counterions butylamine, hexylamine, octylamine, benzylamine, cyclohexylamine, tert-butylamine, 2-amino-2-methylpropan-1-ol, 2-amino-2-methylpropan-1,3-diol andtris(hydroxymethyl)aminomethane. Salt formation was confirmed, the salts were characterized and their corresponding solubilities determined and rationalized with respect to the counterions' properties. Results and conclusion: The properties of the salt highly dependent on the nature of the counterion and, although there is considerable variation, some general conclusion can be drawn. For the alkyl amines series, increasing chain length leads to a reduction in solubility across all the acidic drugs studied and a reduction in melting point, thus contradicting simplistic relationships between solubility and melting point. Small, compact counterions consistently produce crystalline salts with high melting point accompanied with a modest improvement in solubility and the nature of hydrogen bonding between the ions has a major impact on the solubility.

KW - Counterion

KW - Etodolac

KW - Flurbiprofen

KW - Gemfibrozil

KW - Ibuprofen

KW - Salt selection

KW - Solubility

KW - Tris(hydroxymethyl)aminomethane

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M3 - Article

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SP - 93

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JO - Drug Development and Industrial Pharmacy

T2 - Drug Development and Industrial Pharmacy

JF - Drug Development and Industrial Pharmacy

SN - 0363-9045

IS - 1

ER -