Journal ofThermal Analysis, Vol. 51 (1998) 973-980

THERMAL STUDY OF DIFFERENT OMEPRAWLE-y-CD CO-GROUND SYSTEMS

M. J Arias', P. Mufioz', J R. Moyano', J M. Gines' and es. Novize 'Oepartment of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Seville, 410 12-Seville, Spain 2Research Group for Technical Analytical Chemistry, of the Hungarian Academy of Sciences, Technical University ofBudapest, St. Gellert ter 4, Budapest, H-1521

Abstract

Techniques of OSC, TGIDTG, EGO and HSM were used to study and characterize the complex formation and state of dispersion after co-grinding of a 1: 1 mixture of omeprazole (OME) and y-cyclodextrin (y-CD) under various conditions. The changed crystalline proper­ties of the composites obtained by co-grinding suggested distinct types of interactions be­tween the components, as a consequence of the variations in the grinding procedure. The ex­perimental data clearly revealed that a true solid complex OME-y-CD was obtained only by wetting the mixture of the components with phosphate buffer during the co-grinding. Other co-grinding procedures yielded only amorphous drug-CO mixtures or their combination with partial complexation.

Keywords: OSC, EGO, y-cyclodextrin, HSM, omeprazole, TG/OTG

Introduction

Co-grinding is an important industrial process used for the particle size re­duction of drugs, in order to enhance their dissolution rate. In addition to a size reduction, grinding also exerts a striking effect on the properties of the crystals. The grinding efficiency is improved by supplementation with additives. Thus, it is possible to obtain either amorphous mixtures of the co-ground components or inclusion complexes, depending on the characteristics of the starting materials, the drug and the carrier, and on the grinding procedure [1-6].

Omeprazole (OME), 5-methoxy-2-[4-methoxy-3,5-dimethyl-2-pyridyl-methyl-sulfinyl]benzimidazole, is a gastric proton-pump inhibitor, widely used as an antiulcerative for the regulation of gastric acid secretion. Its formulation with cyclodextrins (CDs) is justified since OME is a poorly water-soluble sub­stance, highly unstable at low pH, and thus displays wide interindividual vari­ations in its absorption from the gut.

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974 ARIAS et al.: OMEPRAZOLE-CYCLODEXTRIN SYSTEM

CDs are typical host moleeules which can incorporate a wide variety of for­eign moleeules to form crystalline inclusion complexes [7, 8]. Normally, the physicochemical and (in the case of drugs) biopharmaceutical properties of the incorporated components vary as a result of complexation. In consequence of the complexation of the guest, water moleeules are released from the CD cavity. For this reason, thermal techniques such as DSC, TG/DTG and EGD may give a pre­eise insight into the state of the water and the guest in the CD. HSM may provide complementary visual information concerning experimental evidence of real in­clusion or whether the co-grinding procedure leads only to amorphization of the system.

Experimental

Materials

Micronized OME was a gift from Tedec-Meiji Farma S.A. (Madrid, Spain) and commercial y-CD was provided by Cyclolab (Budapest, Hungary). All other reagents were of analytical reagent grade.

Preparation ofthe sampies

Co-grinding was carried out by milling a 1: 1 OME-y-CD physical mixture in a semi-industrial mill (Fritsch pulverisette, type 02102) during 4 h. Four variants of the method were applied: dry co-grinding (DGM), or wetting of the mixtures with (a) absolute EtOH (EWGM), (b) a 1: 1 EtOH:phosphate buffer solution (EBWGM) or (c) a phosphate buffer (BWGM). The phosphate buffer was used instead of water to wet the systems during the grinding because of the instability of OME at low pH. A physical mixture (PM) and dry-ground OME were used as references. The final products were pulverized and sieved between 50 and 200 11m mesh.

DSC

Sampies of 5 mg were accurately weighed (±O.l mg) and deposited in 45 IlL aluminium pans. The curves were obtained in Ar atmosphere on a DuPont l090 DSC instrument, by heating from 30 to 300°C at 10°C min- I

.

TG/DTG

TG curves were recorded in an inert atmosphere (Ar) on a DuPont 951 ther­mobalance, starting from 5 mg (±O.l mg) sampie mass. The heating rate was 5°C min -1 in the range 30 to 400°C. The same apparatus provided the DTG pro­files on the basis of the recorded TG curves.

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EGD

EGD were performed in a DuPont 916, Carle 3000 TEA apparatus. An initial sampie mass of 3 mg (±O.05 mg) was heated from 30 to 350°C at 8°C min -I under a N2 atmosphere.

HSM

Physical changes in the sampies on heating were monitored by means of a Mettler FP 82 HT hot-stage microscope. A small amount of sampie (approxi­mately 0.1 mg) was placed on a glass slide with a coverglass and heated at 5°C min- I in air atmosphere in the temperature range from 30 to 300°C.

Results and discussion

DSC

The DSC curves of the starting materials and the systems under study are pre­sen ted in Fig. 1. The DSC curve of OME (Fig. 1a) is characterized by the pres­ence of a sharp endothermic effect at 148°C, assigned to the melting of the prod­uct, followed by a broad exotherm at 160°C, due to the decomposition of the drug.

Dry-ground OME (Fig. 1d) displays a melting endotherm at 150°C, although somewhat decreased, evidencing only partial amorphization of the drug during dry-grinding. This result was confirmed by XRD [9].

y-CD alone (Fig. 1 b) exhibits first a broad endothermic effect at 50°C, fol­lowed by a small second endotherm at about 100°C, attributed to the process of dehydration ofthe CD, wh ich contains water-retained moleeules oftwo different types [10]. The decomposition of the sampie started at 275°C in the solid state, and continued in the liquid phase after the melting of y-CD.

The curve corresponding to the OME-y-CD PM (Fig. 1c) is a simple superpo­sition of those of the starting materials, where the drug melting endotherm can be readily observed at 147°C. The dehydration peak temperature is lower than that observed for y-CD. This indicates the dehydration of the partner, al ready ob­served in CD mixtures [11]. In the DSC curve taken from the PM, an exothermic effect was also present after the OME melting peak. This effect has often been as­signed to partial inc1usion compound formation, but in our case it seems to be due to drug decomposition.

The DGM (Fig. 1e) gave a drastically changed DSC profile, presenting a flat appearance, which confirmed the amorphous or poorly crystalline state of the solid phase. Although the absence of the melting peak of a drug in the DSC curves of co-ground sampies has often been interpreted as a consequence of real inc1usion complex formation, this behaviour can in fact be due to the formation

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976 ARIAS et al.: OMEPRAZOLE--CYCLODEXTRIN SYSTEM

of an amorphous solid dispersion and not necessarily to molecular encapsulation inside the CD cavity. Lin et al. [6] found that simple amorphization of the CD and the drug component can mask the melting endotherm of some co-ground drugs. This assumption was corroborated in our case by the EGD results to be presented later, and by the XRD spectra already reported [9]. Moreover, it agrees with our idea that, in most cases, the self-adsorbed water content of the CD is not suffi­cient for areal inclusion complex to be formed during the co-grinding process [12-13].

In contrast, the EWGM (Fig. 1 f) presents the melting endotherm of the drug, clearly evidencing that üME does not form a solid-state complex with y-CD un­der these co-grinding conditions. As water is essential for complex formation, absolute EtüH does not provide the conditions necessary for inclusion of the drug into the CD.

3: E

-:..... :1:\_ "0"0

I , Endo

Temperature / oe

Fig. 1 DSC curves corresponding to OME-y-CD binary systems treated by different co-grind­ing procedures: a) micronized drug, b) y-CD, c) PM, d) dry-ground OME, e) DGM, f) EWGM, g) EBWGM and h) BWGM

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Finally, EBWGM and BWGM (Figs 19 and Ih) present, respectively, a partial and an almost total process of inclusion complexation of OME into y-CD. This was proved by the decrease in the fusion effect and the degradation exotherm of the drug. Moreover, XRD observations [9] supported the idea of the formation of a new crystalline solid phase, the inclusion compound.

TG/DTG

TG/DTG curves of the binary systems and the raw materials are illustrated in Fig. 2. Table 1 summarizes the main thermal events. For OME, the DTG curve re-vealed an appreciable mass loss after fusion, attributed to the degradation of the drug.

Table 1 Summary of the main thermal events recorded by TG/DTG

Water loss Start ofOME 11m at different

temperature Water loss/% TDTG pe./oC interval1°C

decomposition/oC temperatures/oC/%

no adsorbed 230115 170

OME 0 130 250119 257 water 350/45 350

20011.9 167 PM 30-130 7.2 130 220/2.5 330

25014.1

20011.2 164 DGM 30-110 5.2 140 220/2.3 332

250/4.1

20011.8 172 EWGM 30-130 7.6 140 22012.2 331

250/5.5

200/1.4 305 EBWGM 30-150 13.0 150 220/1.7

25013.5

20011.2 309 BWGM 30-150 12.1 160 22011.5

250/2.4

The DTG curves of the PM, DGM and EWGM (Figs 2d, e, f), displaya mass loss, starting at about 130-140°C, due to OME degradation. This is proofthat in these cases true inclusion compounds are not formed. The DTG curves of EBWGM and BWGM (Figs 2g, h) do not exhibit such a marked effect, suggest­ing inclusion complex formation.

EGD

Figures 3a and 3b depict the EGD runs corresponding to micronized OME and dry-ground OME, respectively. Both Figures reveal the beginning of gas

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978 ARIAS et al.: OMEPRAZOLE--CYCLODEXTRIN SYSTEM

Temperature (oe

Fig. 2 DTG runs corresponding to OME-y-CD binary systems treated by different co-grind­ing procedures: a) micronized drug, b) dry-ground OME, c) y-CD, d) PM, e) DGM, f) EWGM, g) EBWGM and h) BWGM

evolution at 150°C, due to drug decomposition. Since the EGD apparatus is un­able to detect the loss of water from any sampIe, the y-CD run (Fig. 3c) simply displays a double peak starting at 290°C, indicating the beginning of CD degra­dation.

In the binary systems, the PM (Fig. 3d) behaves as a simple mixture ofthe two components, OME and y-CD. Similarly, the effect at 150°C due to drug decom­position is present for the DGM and the EWGM (Figs 3e and 3f, respectively), demonstrating that neither of these processing methods leads to inc1usion com­plexation. It is interesting that CD amorphization leads to a single displacement in the degradation of CD, produced slightly earlier. Finally, the EGD traces of the EBWGM and BWGM (Figs 3g and 3h, respectively) indicate the disappearance of the event caused by drug decomposition. Moreover, for the BWGM, only one gas evolution effect at 270°C can be observed, assigned to complex degradation. In contrast, the EBWGM still reveals, although quite masked, the double effect corresponding to free CD degradation.

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> E -... Ö c ~ .:.:h~ ___ _

9

e

d

c

b

a

50 Tempemture loe

Fig. 3 EGO curves corresponding to OME-y-CO binary systems treated by different co­grinding procedures: a) micronized drug, b) dry-ground OME, c) y-CO, d) PM, e) OGM, f) EWGM, g) EBWGM and h) BWGM

HSM

979

The feasibility of the formation of an inclusion complex in the BWGM was corroborated by the HSM study. The examination of pure OME showed that the crystals of the drug first underwent a melting process at about 159°C, followed by immediate degradation at 162°C. The HSM of the OME-y-CD PM succes­sively revealed y-CD dehydration, melting of the drug, partial adsorption of the melt into the mass of CD, degradation of the molten drug, and finally melting of y-CD with decomposition. The same behaviour was observed for the PM and, al­though only slightly insinuated, for the EBWGM, whereas the melting of the drug was not registered in the cases of DGM and BWGM. These results confirm by direct observation the effects recorded by DSC.

* * * The authors would thank the valuable technical assistance of Mrs. E. T6th. The financial sup­

port ofthe OTKA No 014 550 grant and the Soros Foundation is gratefully acknowledged.

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980 ARIAS cl al.: OMEPRAZOLE--CYCLODEXTRIN SYSTEM

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