Enhanced dissolution rate and synchronized release of drugs in binary systems through formulation: Amorphous naproxen–cimetidine mixtures prepared by mechanical activation

Allesø, Morten; Chieng, Norman; Rehder, Sönke; Rantanen, Jukka; Rades, Thomas; Aaltonen, Jaakko

doi:10.1016/j.jconrel.2009.01.027

Cited by 248 publications

(225 citation statements)

References 36 publications

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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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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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“…In contrast, the simvastatin-glipizide co-amorphous mixture showed improved physical stability without evidence of intermolecular interactions as studied by Lobmann et al (19). Alleso et al have illustrated the stabilization of the naproxen-cimetidine amorphous mixtures dictated by molecular-level interactions rather than bulk-level phenomena (20). Therefore, there is a hope and need to rationalize the co-amorphous concept by using a specific clinical dose ratio of pharmacologically relevant drug combinations.…”

Section: Introductionmentioning

confidence: 99%

Co-Amorphous Combination of Nateglinide-Metformin Hydrochloride for Dissolution Enhancement

Wairkar

Gaud

2015

AAPS PharmSciTech

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Abstract. The aim of the present work was to prepare a co-amorphous mixture (COAM) of Nateglinide and Metformin hydrochloride to enhance the dissolution rate of poorly soluble Nateglinide. Nateglinide (120 mg) and Metformin hydrochloride (500 mg) COAM, as a dose ratio, were prepared by ball-milling technique. COAMs were characterized for saturation solubility, amorphism and physicochemical interactions (X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR)), SEM, in vitro dissolution, and stability studies. Solubility studies revealed a sevenfold rise in solubility of Nateglinide from 0.061 to 0.423 mg/ml in dose ratio of COAM. Solid-state characterization of COAM suggested amorphization of Nateglinide after 6 h of ball milling. XRPD and DSC studies confirmed amorphism in Nateglinide, whereas FTIR elucidated hydrogen interactions (proton exchange between Nateglinide and Metformin hydrochloride). Interestingly, due to low energy of fusion, Nateglinide was completely amorphized and stabilized by Metformin hydrochloride. Consequently, in vitro drug release showed significant increase in dissolution of Nateglinide in COAM, irrespective of dissolution medium. However, little change was observed in the solubility and dissolution profile of Metformin hydrochloride, revealing small change in its crystallinity. Stability data indicated no traces of devitrification in XRPD of stability sample of COAM, and % drug release remained unaffected at accelerated storage conditions. Amorphism of Nateglinide, proton exchange with Metformin hydrochloride, and stabilization of its amorphous form have been noted in ball-milled COAM of NateglinideMetformin hydrochloride, revealing enhanced dissolution of Nateglinide. Thus, COAM of NateglinideMetformin hydrochloride system is a promising approach for combination therapy in diabetic patients.

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“…Recently, the formation of co-amorphous stoichiometric mixtures, consisting of either an API and a low molecular weight excipient or two active drug substances, have been shown to be a promising strategy to stabilize the amorphous form of a drug and to date a number of co-amorphous systems with enhanced physicochemical properties have been prepared by co-milling or quench-cooling Allesø et al, 2009;Löbmann et al, 2011;Löbmann et al, 2012;Lu et al, 1998;Masuda et al, 2012;Hoppu et al, 2007;Hoppu et al, 2009). The increased stability is generally attributed to intermolecular interactions such as hydrogen bonding between the API and the coformer or between the two APIs.…”

Section: Introductionmentioning

confidence: 99%

The influence of co-formers on the dissolution rates of co-amorphous sulfamerazine/excipient systems

Gniado

Löbmann

Erxleben

2016

International Journal of Pharmaceutics

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A comprehensive study on the dissolution properties of three co-amorphous sulfamerazine/excipient systems, namely sulfamerazine/deoxycholic acid, sulfamerazine/citric acid and sulfamerazine/sodium taurocholate (SMZ/DA, SMZ/CA and SMZ/NaTC; 1:1 molar ratio), is reported. While all three co-formers stabilize the amorphous state during storage, only coamorphization with NaTC provides a dissolution advantage over crystalline SMZ and the reasons for this were analyzed. In the case of SMZ/DA extensive gelation of DA protects the amorphous phase from crystallization upon contact with buffer, but at the same time prevents the release of SMZ into solution. Disk dissolution studies showed an improved dissolution behavior of SMZ/CA compared to crystalline SMZ. However, enhanced dissolution properties were not seen in powder dissolution testing due to poor dispersibility. Co-amorphization of SMZ and NaTC resulted in a significant increase in dissolution rate, both in powder and disk dissolution studies.

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Enhanced dissolution rate and synchronized release of drugs in binary systems through formulation: Amorphous naproxen–cimetidine mixtures prepared by mechanical activation

Cited by 248 publications

References 36 publications

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

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

Co-Amorphous Combination of Nateglinide-Metformin Hydrochloride for Dissolution Enhancement

The influence of co-formers on the dissolution rates of co-amorphous sulfamerazine/excipient systems

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