From form to function: Crystallization of active pharmaceutical ingredients

Varíankaval, Narayan; Cote, Aaron; Doherty, Michael F.

doi:10.1002/aic.11555

Cited by 259 publications

(250 citation statements)

References 27 publications

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“…Therefore, regulatory approval to sell a drug is given for the drug in a specific polymorph, which must then be reliably produced. For an introduction to pharmaceutical crystallisation see the perspective of Variankaval et al 8 .…”

Section: Ritonavirmentioning

confidence: 99%

The non-classical nucleation of crystals: microscopic mechanisms and applications to molecular crystals, ice and calcium carbonate

Sear

2012

International Materials Reviews

206

219

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Crystals form via nucleation followed by growth. Often nucleation data is interpreted using the classical theory of nucleation, which is essentially a simple theory for the nucleation of a fluid phase. I characterise this classical theory as making six assumptions; I discuss each assumption in turn. I then review experiments and simulations that find nucleation behaviour that cannot be described by the classical theory. The experiments are on the crystallisation from solution of molecules such as drugs and related molecules, ice and calcium carbonate. The review also covers work on non-classical nucleation in solutions of the protein lysozyme, and work on the fascinating phenomenon of nucleation induced by laser pulses. I hope this review will be of interest to those studying the crystallisation of both molecules and ions from solution. The review aims to advance our understanding of the crucial first step in crystallisation, and to enable researchers studying crystallisation in one system to learn from what others have done in studying analogous phenomena in different systems.

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Section: Ritonavirmentioning

confidence: 99%

The non-classical nucleation of crystals: microscopic mechanisms and applications to molecular crystals, ice and calcium carbonate

Sear

2012

International Materials Reviews

206

219

View full text Add to dashboard Cite

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“…In this case the growth of each face of the crystal was more uniform, as expected when each particle is formed from a single droplet of solution and indicates that spray drying may be useful as a crystallisation process to overcome the crystal habit issues associated with elongated needles. 51 The morphology of CS-I based on SCXRD data indicated that prisms were formed and were composed of three major planes: (141), (101) and (001) …”

Section: Morphology Of the Saltsmentioning

confidence: 99%

Formation and Physicochemical Properties of Crystalline and Amorphous Salts with Different Stoichiometries Formed between Ciprofloxacin and Succinic Acid

Paluch¹,

McCabe²,

Müller‐Bunz

et al. 2013

Mol. Pharmaceutics

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Multi-ionisable compounds, such as dicarboxylic acids, offer the possibility of forming salts of drugs with multiple stoichiometries. Attempts to crystallise ciprofloxacin, a poorly water soluble, amphoteric molecule with succinic acid (S) resulted in isolation of ciprofloxacin hemisuccinate (1:1) trihydrate (CHS-I) and ciprofloxacin succinate (2:1) tetrahydrate (CS-I). Anhydrous ciprofloxacin hemisuccinate (CHS-II) and anhydrous ciprofloxacin succinate (CS-II) were also obtained. It was also possible to obtain stoichiometrically equivalent amorphous salt forms, CHS-III and CS-III, by spray drying and milling, respectively, of the drug and acid. Anhydrous CHS and CS had melting points at ~215 and ~228 °C, while the glass transition temperatures of CHS-III and CS-III were ~101 and ~79 °C, respectively. Dynamic solubility studies revealed the metastable nature of CS-I in aqueous media, resulting in a transformation of CS-I to a mix of CHS-I and ciprofloxacin 1:3.7 hydrate, consistent with the phase diagram. CS-III was observed to dissolve non-congruently leading to high and sustainable drug solution concentrations in water at 25 and 37 ºC, with the ciprofloxacin concentration of 58.8±1.18 mg/ml after 1 hour of the experiment at 37 ºC. This work shows that crystalline salts with multiple stoichiometries and amorphous salts have diverse pharmaceutically-relevant properties, including molecular, solid state and solubility characteristics.

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“…The use of this modular ionic liquids-based strategy to produce tuneable active pharmaceutical ingredients is very attractive since it allows infinite new possibilities, challenges and opportunities. Besides the elimination of polymorphism and the adjustable solubility, the question of how ionic liquids conjugated with pharmaceutical ingredients could enhance the transport across the membrane is of interest within the APIs context (Dean et al, 2009;Stoimenovski and MacFarlane, 2011;Stoimenovski et al, 2010;Variankaval et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of solubility and partition properties of ampicillin-based ionic liquids

Florindo

Araújo

Alves

et al. 2013

International Journal of Pharmaceutics

107

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a b s t r a c tIn order to overcome the problems associated with low water solubility, and consequently low bioavailability of active pharmaceutical ingredients (APIs), herein we explore a modular ionic liquid synthetic strategy for improved APIs. Ionic liquids containing l-ampicillin as active pharmaceutical ingredient anion were prepared using the methodology developed in our previous work, using organic cations selected from substituted ammonium, phosphonium, pyridinium and methylimidazolium salts, with the intent of enhancing the solubility and bioavailability of l-ampicillin forms. In order to evaluate important properties of the synthesized API-ILs, the water solubility at 25 • C and 37 • C (body temperature) as well as octanol-water partition coefficients (K ow 's) and HDPC micelles partition at 25 • C were measured. Critical micelle concentrations (CMC's) in water at 25 • C and 37 • C of the pharmaceutical ionic liquids bearing cations with surfactant properties were also determined from ionic conductivity measurements.

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From form to function: Crystallization of active pharmaceutical ingredients

Cited by 259 publications

References 27 publications

The non-classical nucleation of crystals: microscopic mechanisms and applications to molecular crystals, ice and calcium carbonate

The non-classical nucleation of crystals: microscopic mechanisms and applications to molecular crystals, ice and calcium carbonate

Formation and Physicochemical Properties of Crystalline and Amorphous Salts with Different Stoichiometries Formed between Ciprofloxacin and Succinic Acid

Evaluation of solubility and partition properties of ampicillin-based ionic liquids

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