Investigation of the Milling-Induced Thermal Behavior of Crystalline and Amorphous Griseofulvin

Trasi, Niraj S.; Boerrigter, Stephan X. M.; Byrn, Stephen R.

doi:10.1007/s11095-010-0129-3

Cited by 58 publications

(60 citation statements)

References 26 publications

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“…Similar thermal behavior has been observed for another compound, etravirine, where cryomilling resulted in an amorphous solid exhibiting a double exotherm in the crystallization event (16). However, upon further examination of the double exotherm, it was concluded that griseofulvin actually forms an amorphous state on milling and that the double exotherms coincide with two distinct events: crystallization of nucleated surfaces and subsequent crystallization of the bulk and non-nucleated surfaces (17). The question why compounds such as griseofulvin may exhibit this interesting type of crystallization behavior and what underlying physicochemical properties are responsible for it remains unanswered to date.…”

Section: Introductionsupporting

confidence: 65%

“…This difference in crystal growth rates reduces as the temperature is increased with no differences to be seen above a certain temperature. In a previous publication of our group, surface crystallization has been suggested to be the most probable explanation for the appearance of a double exotherm observed upon heating cryomilled griseofulvin (17). Upon comparison of the surface crystal growth rates of the different compounds used in this study (Fig.…”

Section: Discussionmentioning

confidence: 62%

“…After 30 min, it could be clearly seen that two separate exothermic thermal events were obtained leading to the formation of a double exotherm which became even more pronounced after 60 min resulting in an overall recrystallization enthalpy of around 44 J/g. As shown in a previous publication, the first exotherm is due to the crystallization of particles having nuclei on their surface (surface crystallization); the second exotherm corresponds to crystallization of particle surfaces without nuclei along with the crystallization of the interior of the particles (bulk crystallization) (17). The fact that a considerable increase in surface self-diffusion relative to bulk diffusion occurs at temperatures close to T g results in the surface crystallization occurring close to and sometimes overlapping the glass transition event (19).…”

Section: Griseofulvinmentioning

confidence: 59%

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Mechanically Induced Amorphization of Drugs: A Study of the Thermal Behavior of Cryomilled Compounds

Trasi

Byrn

2012

AAPS PharmSciTech

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Abstract. The purpose of this work was to determine what aspect of the milled compound influences its thermal profile. For this, six different compounds with different properties were chosen and cryomilled for different times to get an amorphous solid. Differential scanning calorimetry (DSC) and X-ray powder diffraction were used to characterize the material and look at the thermal behavior. Melt-quenched samples were also prepared, and the thermal profile upon milling was determined and correlated with the thermal behavior of the cryomilled samples. Growth rates were determined by hot-stage microscopy. Ketoconazole, when cryomilled, showed only one crystallization exotherm in the DSC profile. Ursodiol, and to some extent indomethacin, initially showed a double exotherm which eventually become a single exotherm on further milling. Griseofulvin, carbamazepine, and piroxicam exhibited a double exotherm in the DSC profile upon cryomilling to the amorphous state. Surface crystal growth rates around T g were found to be highest for compounds showing the double exotherm in the DSC. Thus, it was seen that compounds which have high surface crystallization tendency will exhibit the double exotherm during heating.

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Section: Introductionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 62%

Section: Griseofulvinmentioning

confidence: 59%

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Mechanically Induced Amorphization of Drugs: A Study of the Thermal Behavior of Cryomilled Compounds

Trasi

Byrn

2012

AAPS PharmSciTech

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“…7 It has been observed that milling a material below its Tg favours amorphisation. Several APIs including salbutamol sulphate 8 , cimetidine 9 and griseofulvin 10 were amorphised upon milling. In contrast, milling at elevated temperatures above the Tg value for mannitol 11 , sorbitol 11 and indomethacin 12 resulted in crystalline products but of a different polymorph.…”

Section: Introductionmentioning

confidence: 99%

Investigation of the Capacity of Low Glass Transition Temperature Excipients to Minimize Amorphization of Sulfadimidine on Comilling

Curtin

Amharar

et al. 2012

Mol. Pharmaceutics

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The co-processing of active pharmaceutical ingredient (API) with an excipient which has a high glass transition temperature (Tg) is a recognised strategy to stabilise the amorphous form of a drug. This work investigates whether co-processing a model API, sulfadimidine (SDM) with a series of low Tg excipients prevents or reduces amorphisation of the crystalline drug. It was hypothesised that these excipients could exert a Tg lowering effect, resulting in composite Tg values lower than that of the API alone and promote crystallisation of the drug. Milled SDM and co-milled SDM with glutaric acid (GA), adipic acid (AA), succinic acid (SA) and malic acid (MA) were characterised with respect to their thermal, X-Ray diffraction, spectroscopic and vapour sorption properties.SDM was predominantly amorphous when milled alone, with an amorphous content of 82 %.No amorphous content was detected by dynamic vapour sorption (DVS) on co-milling SDM with 50 % w/w GA, and amorphous content of the API was reduced by almost 30 %, relative to the API milled alone, on co-milling with 50 % w/w AA. In contrast, amorphisation of SDM was promoted on co-milling with 50 % w/w SA and MA, as indicated by near infrared (NIR) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 spectroscopy. Results indicated that the API was completely amorphised in the SDM:MA comilled composite.The saturated solubility of GA and AA in the amorphous API was estimated by thermal methods.It was observed that the Tg of the co-melt quenched composites reached a minimum and levelled out at this solubility concentration. Maximum crystallinity of API on co-milling was reached at excipient concentrations comparable to the saturated concentration solubility of excipient in the API. Moreover, the closer the Hildebrand solubility parameter of the excipient to the API, the greater was the inhibition of API amorphisation on co-milling.The results reported here indicate that an excipient with a low Tg coupled with high solubility in the API can prevent or reduce the generation of an amorphous phase on co-milling.

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“…DSC studies have revealed the atypical bimodal crystallization of milled amorphous griseofulvin wherein the first exotherm occur prior to the T g (Trasi and Byrn 2012;Trasi et al 2010;Willart et al 2012). Such behavior was also noticed for other milled amorphous form of felodipine, sulfamerazine, piroxicam, hydrochlorothiazide (Chattoraj et al 2012).…”

Section: Crystallization Melting Crystallinity and Mixing Interactmentioning

confidence: 78%

Structural Characterization of Amorphous Solid Dispersions

Paudel

Meeus

Mooter

2014

Advances in Delivery Science and Technology

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Investigation of the Milling-Induced Thermal Behavior of Crystalline and Amorphous Griseofulvin

Cited by 58 publications

References 26 publications

Mechanically Induced Amorphization of Drugs: A Study of the Thermal Behavior of Cryomilled Compounds

Mechanically Induced Amorphization of Drugs: A Study of the Thermal Behavior of Cryomilled Compounds

Investigation of the Capacity of Low Glass Transition Temperature Excipients to Minimize Amorphization of Sulfadimidine on Comilling

Structural Characterization of Amorphous Solid Dispersions

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