Transformation of Pharmaceutical Compounds upon Milling and Comilling: The Role of Tg

Descamps, Marc; willart, Jean-François; Dudognon, Emeline; Caron, Vincent

doi:10.1002/jps.20939

Cited by 204 publications

(159 citation statements)

References 25 publications

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“…It is clear from the FH parameters' values that the greater ability of SMZ (compared to STZ, SDM and SDZ) to form amorphous dispersions with PVP or Soluplus® is not due to a greater miscibility with these excipients compared to the other sulfonamides studied in this article. It has been shown that, the greater the glass transition temperature, the easier the amorphisation of a compound upon milling at a given temperature (19,21,22,32,40,41). However, this cannot explain the amorphisation of SMZ with lower excipient concentration compared to SDM as the Tg of SDM is higher than the Tg of SMZ, and therefore, one might expect that SDM/excipient systems should form amorphous dispersions over a wider concentration range than SMZ/excipient systems.…”

Section: Differing Behaviour Of Smz Compared To Other Sulfonamidesmentioning

confidence: 99%

Amorphous Solid Dispersions of Sulfonamide/Soluplus® and Sulfonamide/PVP Prepared by Ball Milling

Caron

Tajber

et al. 2013

AAPS PharmSciTech

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Abstract. The aim of this paper is to investigate the physicochemical properties of binary amorphous dispersions of poorly soluble sulfonamide/polymeric excipient prepared by ball milling. The sulfonamides selected were sulfathiazole (STZ), sulfadimidine (SDM), sulfamerazine (SMZ) and sulfadiazine (SDZ). The excipients were polyvinylpyrrolidone (PVP) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, commercially known as Soluplus®. Co-milled systems were characterised by powder X-ray diffraction and differential scanning calorimetry. PVP was shown to form amorphous dispersions over a wider composition range than Soluplus® for the four sulfonamides tested. Moreover, amorphous dispersions made with PVP were homogeneous [single glass transition (Tg)], while amorphous dispersions made from Soluplus® were heterogeneous (two Tgs). This behaviour is consistent with the fact that all the sulfonamides tested presented a lower solubility in Soluplus® than in PVP, as evidenced by Flory-Huggins parameters determined. Amorphous dispersions of SDM with Soluplus® could be produced even though SDM does not amorphise alone upon milling and Soluplus® presents Tg at a lower temperature than SDM. Amorphous dispersions of SMZ could be prepared with a lower excipient concentration compared to STZ, SDM and SDZ, which may reflect the one-dimensional H-bonding network in SMZ compared to the 2D or 3D Hbonding network found in the other sulfonamides. Stability tests (60% RH/25°C) revealed that dispersions made with Soluplus® remained dry and powdery compared to those made with PVP that formed a sticky paste in less than 2 weeks, indicating a possible advantage of using Soluplus® in terms of increased physical stability under high humidity storage conditions.

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Section: Differing Behaviour Of Smz Compared To Other Sulfonamidesmentioning

confidence: 99%

Amorphous Solid Dispersions of Sulfonamide/Soluplus® and Sulfonamide/PVP Prepared by Ball Milling

Caron

Tajber

et al. 2013

AAPS PharmSciTech

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“…[1][2][3] When milling a crystalline active pharmaceutical ingredient (API), the mechanical stress during the milling process cannot only change the particle size, surface area and crystallinity of the API but can also induce polymorphic transformations. [3][4][5][6][7][8][9][10][11] Solid-state polymorphic transitions and amorphization induced by milling have been reported for many pharmaceutical products such as gabapentin, 3 famotidine, 9 ranitidine hydrochloride, 10 and Fananserine. 11 Cryo-milling (Cryogenic grinding) seeks to operate ball milling, a high energy process, at low temperatures with the aid of cryogenic media such as liquid nitrogen.…”

Section: Introductionmentioning

confidence: 99%

“…13 In this paper we describe a detailed study of the effect of cryo-milling on two sulfathiazole polymorphic forms I and III. The physical stability of the amorphous 5 forms produced under different storage conditions has been investigated and the quantitative analysis of binary mixtures of amorphous sulfathiazole with crystalline forms I and III is also constructed to quantify the process induced crystalline disorder in the cryo-milled samples.…”

Section: Introductionmentioning

confidence: 99%

Formation, Physical Stability, and Quantification of Process-Induced Disorder in Cryomilled Samples of a Model Polymorphic Drug

MacFhionnghaile

Caron

et al. 2013

Journal of Pharmaceutical Sciences

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“…These two sugars have been reported to have a sub-ambient glass transition temperature (Kim et al, 1997;Descamps et al, 2007). The DSC scan of melt-quenched XY is presented in Figure 3 and reveals a glass transition at -15.8°C.…”

Section: Thermal Screening On Griseofulvin Based Systemsmentioning

confidence: 97%

“…Hence, the experimental conditions under which GF could be fully amorphised had to be determined. It has been reported in the literature that decreasing the milling temperature favours amorphisation (Descamps et a., 2007). We therefore chose to mill GF at a lower temperature: 4°C.…”

Section: Comillingmentioning

confidence: 99%

Mitigating unwanted amorphisation: A screening method for the selection of suitable excipients

Amharar

Curtin

Gallagher

et al. 2016

European Journal of Pharmaceutical Sciences

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Co-processing an active pharmaceutical ingredient (API) with a low Tg excipient has been previously reported to be an effective strategy for preventing drug amorphisation on milling.This technique relies on the ability of the excipient to form a molecular dispersion with the amorphous API during the milling process. The presence of the excipient within the amorphous phase induces a reduction of the Tg. Hence, the molecular dispersion becomes less stable than the amorphous API alone and recrystallises upon milling. The objective of this study was to develop a screening method for the selection of suitable excipients to prevent amorphisation, based on two criteria: the Tg of the excipient and the solubility of the excipient in the amorphous API. The ability of the excipients to induce Tg reduction was first assessed by measuring the Tg of the amorphous composite by thermal analysis and comparing it with that of the pure API (griseofulvin). A predicted ability for mitigation of amorphisation upon milling was then deduced from these observations for each excipient and assessed against experimental results.The same excipients were then studied with regard to their expected solubility in another amorphous API (budesonide) by Hildebrand solubility parameter calculations in order to 2 evaluate their capacity to form an amorphous composite with the drug. The predicted effects of the excipients on comilling were compared with the amorphous content of the processed API.The screening method as applied to both APIs showed good agreement with the experimental results and were shown to be efficient for the selection of the most appropriate excipient. This approach revealed that the two key parameters involved are the Tg of the excipient and the ability of the API to form an amorphous molecular dispersion with the excipients. This work confirms and completes our previously published results on the mitigation of the amorphisation by comilling with low Tg excipients and constitutes the first report of the use of a polymeric additive for this purpose.

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Transformation of Pharmaceutical Compounds upon Milling and Comilling: The Role of Tg

Cited by 204 publications

References 25 publications

Amorphous Solid Dispersions of Sulfonamide/Soluplus® and Sulfonamide/PVP Prepared by Ball Milling

Amorphous Solid Dispersions of Sulfonamide/Soluplus® and Sulfonamide/PVP Prepared by Ball Milling

Formation, Physical Stability, and Quantification of Process-Induced Disorder in Cryomilled Samples of a Model Polymorphic Drug

Mitigating unwanted amorphisation: A screening method for the selection of suitable excipients

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