Transformation of Pharmaceutical Compounds upon Milling and Comilling: The Role of T g

Transcription

1 Transformation of Pharmaceutical Compounds upon Milling and Comilling: The Role of T g M. DESCAMPS, J.F. WILLART, E. DUDOGNON, V. CARON Laboratoire de Dynamique et Structure des Matériaux Moléculaires. UMR. CNRS University of LILLE1. Bat P Villeneuve d Ascq CEDEX, France Received 9 October 2006; revised 19 December 2006; accepted 22 December 2006 Published online in Wiley InterScience ( DOI /jps ABSTRACT: Milling is a usual process used in the course of drug formulation, which however may change the physical nature of the end product. The diversity of the transformations of organic compounds upon milling has been widely demonstrated in the pharmaceutical literature. However, no effort has still been devoted to study the correlation between the nature of the transformation and the milling conditions. Results clarifying such transformations are shortly reviewed with special attention paid to the temperature of milling. The importance of the position of the glass transition temperature compared with that of milling is demonstrated. It is shown that decreasing the milling temperature leads to an increase of the amorphization tendency whereas milling above T g can produce a crystal-to-crystal transformation between polymorphic varieties. These observations contradict the usual suggestion that milling transforms the physical state only by a heating effect which induces a local melting. Equilibrium thermodynamics does not seem appropriate for describing the process. The driven alloys concept offers a more rational framework to interpret the effect of the milling temperature. Other results are also presented, which demonstrate the possibility for milling to form low temperature solid-state alloys that offer new promising ways to stabilize amorphous molecular solids. ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: , 2007 Keywords: amorphous; X-ray powder diffractometry; solid state; solid solutions; polymorphism; physical stability; milling; materials science; glass; calorimetry (DSC) INTRODUCTION In the course of the solid drugs formulation, molecular compounds are submitted to a large variety of possible perturbations. These perturbations may result in phase transformations or amorphizations of the material. Such physical transformations have direct influence on the stability and solubility of the compounds. 1 Consequently, bioavailability of the drug is prone to changes. Not only these perturbations may Correspondence to: M. Descamps (USTL-UFR de physique, Bat P Villeneuve d Ascq, France. Telephone: ; Fax: ; marc.descamps@univ-lille1.fr) Journal of Pharmaceutical Sciences, Vol. 96, (2007) ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association involve classical thermodynamic variables such as temperature and pressure but also external dynamical forcing. Typical examples of dynamically driven systems are provided by irradiation, milling, extrusion... Usual phase transformations are properly addressed by thermal equilibrium states, equilibrium, and irreversible thermodynamics. However, a general framework that would allow describing and predicting the nature of the end product of dynamically forced pharmaceuticals, is not available. Contrary to metallurgy, 2 6 systematic investigations of mechanically induced transformations of molecular compounds have not yet been done. Over and above the interest to get a better understanding of these transformations for practical reasons in pharmaceutical science, JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007

2 MILLING OF PHARMACEUTICAL COMPOUNDS 1399 there are also fundamental reasons to consider the effect of milling molecular solids to get a better insight in the physics of this kind of process in general. There are several specific properties of molecular compounds which have special relevance in mechanical activation. 1,7,8 Their molecular and crystalline symmetry are generally low, the kinetics of crystallization are often very slow and molecular compounds often show an easy ability to vitrify. Moreover their melting and glass transition temperatures are low and the intermolecular interactions are week. The evolutions of the transport coefficients in the amorphous state often exhibit a strongly nonarrhenius temperature behavior with a dramatic evolution on approaching the glass transition temperature (T g ) ( fragile glass formers ). 9 All these specificities lead to expect a strong sensitivity of molecular compounds to the temperature of milling. From a fundamental point of view molecular compounds certainly offer new interesting situations, which allow testing theoretical approaches. In this article we present some selected results that may help clarifying the behavior pattern of molecular compounds under milling. We have used the interesting opportunity provided by molecular compounds to have their glass transition temperature not far from room temperature to test the importance of the milling temperature with respect to T g. There are several suggestions found in the literature that milling induces an amorphization because it simply results from a local thermal melting followed by a rapid quench. Molecular compounds which are chemically very sensitive to a high temperature excursion allow getting better insight in this aspect. Indeed they may provide an indirect test of the real temperature reached upon milling through their possible degradation. An other suggestion is that amorphization can result from a huge accumulation of defects 10 in the crystal resulting in an increase of its Gibbs free enthalpy. In these conditions the highly defective crystalline phase can become physically less stable than the metastable liquid state so that it amorphizes spontaneously at the temperature of milling. However, the pharmaceutical literature reveals that milling crystals may just as well induce amorphization or transformations to other crystal polymorph. The investigation of the effect of milling on the two polymorphic varieties of sulfamerazine by Grant and coworkers 11 is particularly illustrative from this point of view. They have shown that milling the metastable form II only produces an intensity decrease and a broadening of the X-ray diffraction peaks. No polymorphic transformation was thus observed. On the contrary, form I of sulfamerazine is completely converted to the metastable form II upon a 120 min milling. Form II thus appears to be the result of milling whatever the initial product with no sign of amorphization. Another example is the milling of the different polymorphic varieties of indomethacin (g stable form or a metastable) at room temperature (i.e., close to the glass transition, which is T g 428C). It has been found to induce a transformation to the same final state composed of 50% of the form a and 50% of the amorphous state. The same experiments performed at 48C have been found to induce a total amorphization. 12 Recent cryo-milling experiments on indomethacin 13 also lead to fast amorphization independently of the starting crystalline state. Sometimes more stable states can even be obtained as exemplified by caffeine. 14 A recent study of the factors influencing the complexation of ursodeoxycholic acid with phenanthrene or with anthrone has clearly revealed the influence of the temperature of grinding. 15 The results indicate that complexation is only possible above some grinding temperature while milling at temperature much lower than room temperature prevent the complexation process and results in the amorphization of the ursodeoxycholic acid. Moreover, the idea that milling may drive the crystallites to sizes below the critical radius of nucleation cannot fully explain transformation to other polymorph. By changing the milling temperature we can check whether the amorphization tendency is amplified or not. By milling above the glass transition temperature of the compound we are in position to test whether the transformation still occurs toward an amorphous state which would be that time either rubbery or even fluid. Milling experiments were performed on series of molecular compounds having their glass transition temperature above (trehalose, lactose, budesonide) or below (sorbitol and mannitol) milling temperature (room temperature). Results of experiments in which compounds with very different values of T g were milled together are then presented. This offers one more possibility to check the effect of indirectly changing the glass transition temperature by changing the composition. EXPERIMENTAL Crystalline anhydrous a-lactose was obtained by dehydration of crystalline a-lactose monohydrate. DOI /jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007

3 1400 DESCAMPS ET AL. The dehydration was performed by blowing dry gaseous methanol through 20 g of a-lactose monohydrate during 3 h. The remaining traces of methanol were then removed by placing the sample under vacuum (10 3 mmhg) at 208C during 12 h. Thermogravimetric and NMR 16 measurements have indicated respectively that the a-lactose thus obtained was free of any solvent (water or methanol), and anomer b of lactose. Crystalline a a anhydrous trehalose, mannitol, and G-sorbitol were purchased from Fluka. Their purity are 99.9%, 99.9 %, and 99.5 %, respectively and they were used without further purification. Crystalline budesonide (purity: 99.5%) was kindly provided by AstraZeneca. Ball-milling experiments were performed in a high-energy planetary micro-mill (Pulverisette 7; Fritsch, Idar-Oberstein, Germany) at room temperature. Samples were sealed in Zirconium vials of 45 cm 3 volume with seven balls (Ø 15 mm) of the same materials. The vials are fixed onto a rotation disc and rotate with the same rotation speed O on the opposite direction to the disc, the important feature is thus that the intensity of the mechanical treatment is an increasing function of O. Theapparatus was specially modified to grind hygroscopic samples in a controlled atmosphere. Prior to the milling procedure, the vials were flushed with dry nitrogen gas in order to prevent hydration of the powder during the experiments. To avoid any overheating of the samples, milling periods were alternated with pause periods. The analyses of the milled samples were performed by X-ray diffraction and DSC. MILLING OF PURE CRYSTALLINE COMPOUNDS WELL BELOW THE T g OF THEIR CORRESPONDING LIQUID Milling of Crystalline Anhydrous Disaccharides Trehalose and Lactose These two disaccharides are highly important excipients in drug formulation. 17,18 Trehalose has the very specific character to protect the labile biological molecules both from temperature variations heating or cooling and from dehydration effects. Compare to other disacharides these two sugars have both unusually high glass transition temperature (T g > 1008C). They offer the possibility to explore the effect of milling well below T g. Their T g value is similar to that of number of polymers for which milling would present a risk to affect the molecular integrity. Furthermore, their formulation often involves a stage of particle size reduction and it is useful to know the physical behavior under milling for practical purpose. At room temperature (i.e., about 1008C below their glass transition temperature), using a O value of 400 rpm, these two sugars are completely amorphized after a few hours of milling. Figures 1 and 2 demonstrate that not only the compounds are X-ray amorphous, but also really glassy since a glass transition at T g is found to occur on the DSC scans upon heating the milled materials. The T g values (1208C for trehalose and 1118C for lactose) are found to be similar to that obtained when undercooling the melt. It is important to note that the glassy states which are obtained do not show any trace of caramelization as would be obtained when quench cooling the melt of sugars. It must also be noted that amorphous lactose obtained by the milling route is free of the anomer b. 18 This is not the case for any other amorphization routes (melt-quenching, lyophilization, spray drying...) involving dissolution or heating stages that induce unavoidably a strong mutarotation process giving rise to b-lactose concentrations as large as 50%. There is thus no indication that the amorphization is the result of a local heating above the compound melting point which would be followed by a temperature quench. Milling is really able to promote a direct low temperature crystal to glass transformation. Milling of Crystalline Budesonide The budesonide (22RS 16a,17a-Butylidenedioxypregna-1,4-diene-11b,21-diol-3,20-dione) is a drug used as an anti-inflammatory corticosteroid. 19 Figure 1. X-ray diffraction patterns of trehalose recorded at room temperature before milling (a) and after 20 h of milling treatment with O ¼ 400 rpm (b). DSC heating curves (58C/min) of crystalline trehalose before milling (c) and after 20 h of milling treatment with O ¼ 400 rpm (d). The inset shows a close up view of the glass transition domain of curve d. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007 DOI /jps

4 MILLING OF PHARMACEUTICAL COMPOUNDS 1401 amorphous budesonide is obtained ((b) curve). Upon heating, this glassy system undergoes a glass transition at 908C (see the inset of (d) curve) and then re-crystallises at 1168C. Since it has been shown that there is no noticeable temperature increase upon milling, 18 milling well below their glass transition thus appears to be a very interesting way to obtain amorphous molecular compounds without thermal degradation. Figure 2. X-ray diffraction patterns of lactose recorded at room temperature before milling (a) and after 30 h of milling treatment with O ¼ 400 rpm (b). DSC heating curves (58C/min) of crystalline lactose before milling (c) and after 30 h of milling treatment with O ¼ 400 rpm (d). The curve in inset is a close up view of the glass transition temperature domain of curve d. This crystalline material has been found to be almost insoluble in water (20 mg ml 1 ) at physiological ph (log P ¼ 3.2). 20 To enhance its bioavailability, it is interesting to investigate possibilities to formulate it in its amorphous state since it is known that the solubility can be significantly increased in this latter state. Amorphous budesonide can be obtained by quench from the liquid state. The glass transition temperature is then observed at about 908C. However, as many other pharmacological compounds, budesonide undergoes a thermal degradation before the melting temperature (T m ¼ 2508C) is reached. It is thus interesting to search for other amorphization routes for this compound. The effect of milling budesonide at room temperature, that is, well below T g was thus investigated. Figure 3 shows that, after a 15 h milling at room temperature (O ¼ 400 rpm), a completely MILLING OF PURE CRYSTALLINE COMPOUNDS ABOVE THE T g OF THEIR CORRESPONDING LIQUID Milling of Crystalline D-Sorbitol Figure 4 shows that milling the G crystalline form of D-Sorbitol during 10 h at room temperature (i.e., above T g which is 08C) promotes a progressive conversion to the metastable crystalline form A. 21 The X-ray analysis of the nanostructure evolution upon milling has shown a clear reconstruction of the ultimate crystallites. In the first stage of milling (t < 1 h) a broadening of the diffraction peaks reveals a stage of nanostructuration of the crystallites. This is confirmed by the decrease of the melting temperature of the G Figure 3. X-ray diffraction patterns of budesonide recorded at room temperature before milling (a) and after 15 h of milling treatment with O ¼ 400 rpm (b). DSC heating curves (58C/min) of crystalline budesonide before milling (c) and after 15 h of milling treatment with O ¼ 400 rpm (d). The inset shows a close up view of the glass transition domain appearing on the MDSC in-phase flow (modulation of C/min). Figure 4. Evolution of the X-ray diffraction patterns of sorbitol (G crystalline form) in the course of a 10 h milling process. It shows the progressive conversion of the G phase toward the A phase. DOI /jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007

5 1402 DESCAMPS ET AL. phase which is an indirect proof of the crystallite size reduction. This behavior (Gibbs Thomson effect 22,23 ) predicts a depression (DT m ) of the melting point (T m ) for a decreasing crystallite size (d) which is given by: DT m ¼ 4sT m ð1þ ddh m r s where s is the solid liquid interfacial energy, DH m the bulk energy of melting, and r s the density of the solid. Then, in the second stage, the peaks of the new polymorph appear (t > 2h) and are also broad. After a long enough milling, the Bragg peaks of the appearing new form progressively become very sharp. This shows that milling is able at that time to promote a total reconstruction of the new long-range order on a large microstructural scale. It is not totally clear whether a very transient stage of amorphization mediates between these two polymorphs. This is suggested by the fact that some transport of matter is necessary for the crystalline reconstruction to operate. However, there is no direct evidence of such a stage through the appearance of an amorphous halo in the X-ray pictures or through a glass transition event in the thermograms. This is certainly a very important point to elucidate in order to know if a direct solid-state reconstruction induced by milling is possible. If not, a mechanism of nucleation and growth of crystals in the metastable liquid would prevail. In such a case it would be necessary to accommodate the very small fraction of liquid that may be assume from experiments with the slowness of the kinetics of the process. Milling of Crystalline Mannitol A similar polymorphic transformation was observed when milling the crystalline form of another polyol: the mannitol at room temperature (i.e., above T g which is 138C). 24 The X-ray diffraction patterns on Figure 5a,b show that upon milling, the stable crystalline form b of mannitol undergoes a polymorphic transformation toward the metastable form a. The X-ray diffraction patterns in Figure 5d,e reveal that the polymorphic form b of mannitol undergoes the same transformation upon milling. However, in both cases the form d obtained by milling slowly reverses toward the stable crystalline form a during a RT annealing following the milling process (Fig. 5c,f). These results thus reveal that, Figure 5. X-ray diffraction patterns of mannitol recorded at room temperature: (a) (c) corresponds respectively to mannitol b before milling, after milling (3 h), and after a RT storage (8 days). The milling of the form b induces a conversion toward the form a which reverses toward the form b during the subsequent storage. (d) (f) corresponds respectively to mannitol d before milling, after milling (3 h), and after a RT storage (1 day). The milling of the form d induces a conversion toward the form a which reverses toward the form b during the subsequent storage. using the same milling parameters (temperature and intensity) but starting with different physical state, the milling process leads to a stationary state which is independent of the physical state of the initial material. DISCUSSION Most often it is the amorphization induced by milling that is discussed. Over and above the hypothesis of an induced local heating, it is often suggested that the introduction of defects in the crystal induces a progressive destabilization of the latter with respect to the liquidlike structure. 25 Eventually an amorphous solid is produced when milling is performed below T g. Above T g this way of reasoning predicts a melting to a liquid. Our results show that milling a crystal JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007 DOI /jps

6 MILLING OF PHARMACEUTICAL COMPOUNDS 1403 above T g repetitively produces a polymorphic transformation. We have other results, to be published, which show that a slight milling of a glass just below T g induce crystallization. 26 In the cases presented in this article, the polymorphic transformations which are observed drive the crystal to a more metastable state. This could suggest that milling automatically pushes the system toward states that have higher free enthalpy. However, there are published results in particular caffeine 14 where the reverse situation has been observed: milling transforms the compound in a more stable crystalline phase. This situation is similar to that of millinginduced crystallization mentioned above. Milling is certainly expected to induce a disorder by shearing a compound. However, to explain the full pattern of observed behaviors a more universal approach is necessary. A simple thermodynamic equilibrium picture does not seem satisfying. From the results described above it looks as if temperature is unable to restore a crystalline equilibrium when milling proceeds in the low temperature domain of the sample where large amplitude molecular motions are essentially frozen. On the other hand, at temperature above T g where an amorphous state can exist as a metastable liquid, the molecular mobility is known to be much higher and to increase rapidly with temperature. Because of this higher mobility the restoration of a crystallographic order upon milling is expected to be more efficient. This set of observations suggests that the results can be interpreted in the framework of the driven material concept of Martin and Bellon. 6 According to this model the full process involves a competition between ballistic disordering process, which is independent of temperature (T), and a thermally activated restoration. It has thus been proposed by Martin and Bellon 6 that the state reached upon milling, is identical to the equilibrium state of the nonmilled material at an effective temperature T eff given by the following relation: T eff ¼ T 1 þ D bal ð2þ D th where D bal is the ballistic diffusion coefficient which depends on the forcing intensity and not on temperature. D th is the thermal diffusion coefficient possibly modified by the occurrence of created defects. At low enough temperature, thermal diffusion is expected to be low enough so that the effective temperature under milling becomes higher than the equilibrium melting temperature. This may explain that the lower the temperature of milling the easier the amorphization. COMILLING AND MANIPULATION OF THE AMORPHOUS STATE In this series of milling experiments we have comilled individual crystalline compounds having different values of their T g in the amorphous state. As model systems we have taken lactose/ mannitol and lactose/budesonide mixtures whose thermodynamic characteristics and behavior upon milling were described above. The practical objective of this investigation is to test the possibility to directly prepare molecular alloys at low temperature. This is particularly important for pharmaceutical compounds which are unstable at high temperature and would not support a high temperature alloying. Lactose is a good representative of such a temperature sensitive excipient even if possible reactions with the amine functionality have to be considered when formulating in the amorphous state. A more fundamental objective is to further investigate the effect of temperature on the end product of milling by changing the fractions of the compounds and thus the expected value of T g of a possible glassy alloy with regard to room temperature. Mixed Compounds (Lactose) 1 x (Mannitol) x Figure 6 shows the DSC scans recorded upon heating of quenched liquid mannitol (a), milled lactose (c), and comilled lactose/mannitol crystalline mixture (molar fraction of mannitol: x ¼ 0.39) (b). It must be noticed that, contrary to lactose, the glass transition of mannitol (T g ¼ 138C) is located below the milling temperature. The first event in the last thermogram is a C p jump characteristic of a glass transition located at T g (x ¼ 0.39) ¼ 658C, that is, between those of pure mannitol and pure lactose. Absolutely no sign of glass transition corresponding to pure mannitol or pure lactose can be detected at 138C and 1118C (see run (a) and run (c) corresponding to the pure compounds for comparison). This single glass transition indicates that the amorphous mixed sample obtained by milling is characterized by a single relaxation process. The mixing of the two kinds of molecules has thus really been performed DOI /jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007

7 1404 DESCAMPS ET AL. Figure 6. DSC scans recorded upon heating (58C/ min) of (a) quenched liquid mannitol. (b): lactose/ mannitol crystalline mixture (mannitol fraction x ¼ 0.39) after a 12 h milling process. (c): initially crystalline a-lactose after a 30 h milling process. at the molecular level, giving rise to a true molecular alloy formed in nonequilibrium conditions. Upon heating, crystallization is observed followed by two endotherms corresponding respectively to the melting of the eutectic and a lactose rich solid solution. Mixed Compounds (Lactose) 1 x (Budesonide) x Figure 7 presents the DSC scans recorded upon heating (at 58C/min) of milled lactose (a), milled budesonide (c) and comilled lactose/ budesonide crystalline mixture (budesonide molar fraction x ¼ 0.44) (b). At room temperature, these materials are amorphous. The C p jumps that are characteristic of the glass transition can clearly be observed on the in phase flow of the MDSC scan (modulation of C/min) (inset of Fig. 7). The glass transition of the comilled mixture appears at 1028C. The finding of a single glass transition located between those of pure milled budesonide ((c) scan) and pure milled lactose ((a) scan) indicates that the comilling of budesonide and lactose blends leads to the formation of a molecular alloy with a unique glass phase. As in the case of comilled compound lactose/mannitol, it emphasizes that the mixing of the two molecular species has really been performed at the molecular level so that the mixture is characterized by a unique relaxation process and thus behaves as a single amorphous phase. At higher temperatures, two crystallization peaks can be seen on the DSC scan (b). The first Figure 7. DSC scans recorded upon heating (58C/ min) of: (a) initially crystalline a-lactose after a 12 h milling process. (b): lactose/budesonide crystalline mixture (budesonide weight fraction ¼ 0.5) after a 15 h milling process. (c): initially crystalline budesonide after a 15 h milling process. The inset presents the in-phase flow of the corresponding MDSC scans (modulation of C/min). one is located at 1258C and the second one at 1628C. These temperatures almost correspond to the crystallization temperatures of pure compounds. Investigations are actually in progress to analyze the exact nature of the recrystallization process with respect to the complex melting pattern. Composition Dependence of the Glass Transition The possibility to form molecular alloy has been investigated in the whole range of concentrations for both lactose/budesonide and lactose/mannitol mixtures. For lactose/budesonide the molecular alloy was found to be formed whatever the molar fraction x of budesonide. This behavior was consistent with the fact that the two compounds can be fully amorphized when separately milled. The evolution of the glass transition temperature of the alloy against the budesonide concentration x is reported in Figure 8. It obeys the Gordon Taylor law, 27 which generally describes the concentration dependence of the glass transition in the alloys obtained by thermal quench: T g ðxþ ¼ xt g bud þ Kð1 xþt glact ð3þ x þ Kð1 xþ where K is a fitting parameter. In this case K is found to be equal to JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007 DOI /jps

8 MILLING OF PHARMACEUTICAL COMPOUNDS 1405 Figure 8. Evolution of the glass transition temperature of the comilled mixture of lactose/budesonide versus the budesonide content (&). The solid line represents the Gordon s fitting law. The dot-line is a guide for the eyes. Contrary to the lactose/budesonide mixtures, lactose/mannitol mixtures cannot form molecular alloys upon RT milling in the whole range of concentration in mannitol. Molecular alloy can only be obtained for mannitol fraction x lower than Figure 9 shows that in this concentration range the evolution of T g with the mannitol concentration is well described by the Gordon Taylor law (1) with a fitting parameter K close to For larger mannitol fraction the state obtained after milling is in fact a mixture of lactose/mannitol glass solution and crystalline mannitol a. The extrapolation of the T g (x) curve in Figure 9 indicates that for x > 0.50 the glass transition temperature of the alloy becomes close to the milling temperature. In these conditions, the molecular mobility of the alloy becomes high enough to trigger the crystallization of the chemical component, which is responsible for the plastization of the alloy during the milling process. When the T g of the alloy reach the milling temperature, further amorphization of mannitol is thus probably counterbalanced by a rapid recrystallization toward the form a leading to a steady state concentration of mannitol in the glass solution. This mechanism is coherent with the fact that the phase a is known to arise systematically from the recrystallization of the undercooled liquid mannitol. Milling devices generally operate at room temperature or at the liquid nitrogen temperature. It is thus really difficult to perform systematic investigations of the effects of milling with temperature. It is in particular difficult to decide whether the duality amorphization/polymorphic transformation upon milling is driven or not by the position of the milling temperature with respect to the glass transition of a given compound. In our investigations, this difficulty has been overcome by milling at room temperature a binary mixture whose glass transition temperature can be tuned on either side of the milling temperature by changing the concentration of the two chemical components. Our investigations of the lactose/ mannitol mixtures for which the T g can be tuned from C clearly show that the amorphization process upon milling is replaced by a polymorphic transformation when the T g of the mixture becomes lower than the milling temperature. SUMMARY Figure 9. Evolution of the glass transition temperature of the comilled mixture of lactose/mannitol versus the mannitol content (&). The solid line represents the Gordon s fitting law. The dot-line is a guide for the eyes. Transformations of molecular crystals induced by milling are reported in this article. Specific attention is paid to the position of T g with respect to the temperature of milling. It should be underlined that we took care to use a milling procedure which includes long pause periods in order to keep the milling temperature close to the room temperature and limit overheating. The two main tendencies which emerge from this work are the following: (i) Milling crystalline compounds well below the glass transition temperature of the DOI /jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007

9 1406 DESCAMPS ET AL. corresponding liquid induces a direct solid state vitrification (cases of lactose, 18 trehalose, 17 and budesonide 19 ). This amorphization process is fundamentally different from the usual thermal quench of the melt as proved, for example, by the total absence of caramelization and mutarotation in amorphous lactose obtained by milling. (ii) Milling crystalline compounds above T g may induce polymorphic transformations which generally place the system in a metastable states (cases of sorbitol, 21 mannitol, 24 sulfamerazine 11 ). It is however necessary to qualify the effect of the relative position of T g with respect to the milling temperature on the nature of the end product. A first reason is associated to the definition of the glass transition itself. It is basically not a thermal equilibrium event but the manifestation of the change from an ergodic (above T g ) to a nonergodic (below T g ) situation. The position of the C p jump which marks the glass transition is thus dependent on the temperature scanning rate: for a given compound, the higher the cooling rate, the higher the T g. In that sense, the comparison of the milling temperature with T g is only a way to locate it with regard to the transformation range. The width of this zone is itself very dependent of the fragility, the nonexponentiality and the nonlinearity of the dynamics of the glass former. Another point to be noted is that when not far below T g the nature of the transformation upon milling depends on the intensity of milling. 26 For example, milling the g form of indomethacin at room temperature (i.e., T g 208C) may either induce an amorphization at high intensity or a polymorphic transformation at low intensity. On the other hand, it has been shown that the indomethacin is prone to fast amorphization 13 when milled at nitrogen temperatures. Decreasing the temperature thus appears to have the same effect with regard to the end product of milling than increasing the energy of milling (by increasing the vial rotation speed for instance). In order to understand these behaviors we need to take into account in details the evolution of the thermal diffusion coefficient as a function of temperature, which is particularly very fast near T g for the fragile glass formers usually used in pharmaceuticals. Consequently, the tendencies which are observed are the following: amorphizations when the milling is performed far below T g (at high enough intensity), and polymorphic transformations (if any) when the milling is performed above T g. In the glass transition range both transformations can occur depending on the milling intensity. These observations may have interesting consequences concerning the definition of operative procedure of formulation. For instance, a process which leads to decreasing the glass transition temperature may hinder the amorphization tendency under milling. This is true for milling under humidity and probably the reason which makes that propellant milling is able to promote crystal reconstruction. A conventional thermodynamical approach is thus not sufficient to justify the whole pattern of observed transformations. A nonequilibrium approach such as that proposed for irradiationinduced transformations 6 should be appropriate to provide a satisfying description of all of the observations. ACKNOWLEDGMENTS The authors thank Dr. Thomas Larsson for very useful discussions concerning lactose and binary phase diagrams of molecular compounds. The authors also thank Dr. G. Martin and Prof. P. Bellon for very useful discussions concerning driven materials. This work was performed in the framework of an INTERREG network ( Therapeutic Materials ) between Nord-Pas de Calais, Haute Normandie and Kent (financially supported by the FEDER). We also thank F. Danède and F. Capet for their technical management of the present work. REFERENCES 1. Shakhtshneider TP, Boldyrev VV Mechanochemical synthesis and mechanical activation of drugs. In: Boldyreva E, Boldyrev V, editors. Reactivity of molecular solids. Chichester, UK: John Wiley & Sons. pp Suryanarayana C Mechanical alloying and milling. Prog Mater Sci 46: Ma E Alloys created between immiscible elements. Prog Mater Sci 50: Witkin DB, Lavernia EJ Synthesis and mechanical behavior of nanostructured materials via cryomilling. Prog Mater Sci 51: Le Caer G, Ziller T, Delcroix P, Bellouard C Mixing of iron with various metals by high-energy JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 5, MAY 2007 DOI /jps

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