The effect of co-spray drying with polyethylene glycol on the polymorphic state of mannitol carrier particles for dry powder inhalation

Atsutoshi Ito, Mitsuhide Tanimoto, Hideki Yano, Michiko Kumon, Kazuhiro Inoue, Shuichi Yada, Naoki Wakiyama

Formulation Technology Research Laboratories, Daiichi Sankyo Co., Ltd., 1-2-58, Hiromachi, Shinagawa- ku, Tokyo 140-8710, Japan

Summary

The design of a carrier particle is important for the development of dry powder inhalation (DPI) formulations. Most DPI formulations rely on lactose as a carrier particle; however, lactose has several disadvantages with DPI formulations. In this study we focused on mannitol as an alternative carrier to lactose. Spray drying was reported as challenging to produce α-mannitol, as β-mannitol is obtained in almost all cases. The polymorphic state of a carrier particle is reported as one of the properties which affect the aerosolization performance of DPI formulations. To control the polymorphic state and to evaluate its effect for the aerosolization performance was considered to be important for the development of DPI formulations. The purpose of this study is to control the polymorphic state and to selectively produce α- mannitol by spray drying, instead of β-mannitol. The effect of polyethylene glycol (PEG) 4000 on a polymorphic state of mannitol was investigated. Powder X-ray diffraction studies showed that spray drying mannitol without PEG 4000 completely produced β-mannitol. In contrast, mannitol/PEG 4000 (PEG 4000 concentration was above 1%) co-spray dried products were found to be completely α-mannitol. It can be estimated that the molecular mobility of mannitol in the presence of PEG 4000 must have been slower than that of mannitol alone and reduced molecular mobility inhibited the transformation from α-mannitol nuclei into β-mannitol nuclei during the spray drying process. Consequently, controlling the polymorphic state and selectively producing α-mannitol by spray drying was successful by adding above 1% of PEG 4000.

Introduction

In drug-carrier DPI formulations, the carrier particles form a fundamental component due to low concentrations of the drug. Therefore, a slight change in carrier physicochemical properties is likely to have a considerable effect on aerosolization behavior of DPI formulations. The design of the carrier particle is important for the development of DPI formulations (1, 2). Lactose is the most common and frequently used carrier in DPIs formulation and currently various inhalation grades of lactose with different physical properties are available on the market. The advantages of lactose are its well-investigated toxicity profile, physical and chemical stability, compatibility with drug substances, broad availability and relatively low prices (3, 4). However, the use of lactose has some disadvantages. Due to clinical issues, lactose cannot be used for drug delivery with a diabetic patient. From the view point of compatibility with drug substances, lactose cannot be used for compounds that interact with reducing the sugar function of the lactose, such as formoterol, budesonide or peptides and proteins (5). In addition, lactose is produced from bovine or with bovine-driven additives so that the transmissible spongiform encephalopathy (TSE) is still an issue for this compound (6). Lactose has also easily become partially or fully amorphous upon mechanical treatment such as milling or spray drying, which causes the substance to be unstable for this particle generation process due to the risk of instability during storage. Other excipients such as mannitol have been suggested as possible alternative carriers for DPI formulations (7, 8). Mannitol is an attractive alternative carrier to lactose because it does not involve a reducing sugar function; it is less hygroscopic than some of the other sugars (9) and provides a suitable sweet after-taste which may be beneficial to patients in confirming that the dose has been properly administered (10). Unlike lactose, mannitol does not become partially or fully amorphous upon mechanical treatment such as milling or spray drying (11). Therefore mannitol was the focus as a carrier particle in this study.

The characteristics of carrier particles must be well controlled in terms of size, shape roughness, surface energy, etc. Previously, α-mannitol recrystallized from either acetone or ethanol was also reported to show superior aerosolization performance compared to ground β-mannitol (12). The polymorphic state of a carrier particle is also considered to be one of the properties which affect the aerosolization performance of DPI formulations. In general, spray drying can be used to produce dry powders from solutions, suspensions or emulsions, with greater control over particle size, morphology, crystallinity and powder density. Indeed, spray drying has been used by a number of researchers to generate dry powders suitable for inhalation (3). Though the morphologies of the spray dried mannitol particles such as particle size, shape, and surface roughness could be successfully modified (13), controlling the polymorphic state of mannitol particles by spray drying was reported as challenging, as only β-mannitol was obtained in almost all cases (14). In other words, the method of controlling the polymorphic state of mannitol and selectively producing α-mannitol by spray drying has not been conducted, yet nevertheless spray drying is considered to be a suitable method for manufacturing inhalation particles.

In this study, we tried to control the polymorphic state of mannitol and selectively produce α-mannitol by spray drying. The influences of the sprayed droplet drying rate and the mannitol molecule nucleation rate during the spray drying process to the polymorphic state were investigated by changing these rates through the addition of organic solvents or polyethylene glycol 4000.

Materials and Methods

Mannitol (β-mannitol) and Polyethylene glycol (PEG) 4000 were purchased from Merck Co., Ltd. and Wako Pure Chemicals Industries, Ltd., respectively. Intact Mannitol was used as the reference β-mannitol. The reference α-mannitol was prepared by dissolving mannitol into 70% ethanol until a clear solution was obtained. The solution was slowly cooled down to room temperature and then further cooled in the refrigerator for approximate 12 h. The received crystals were filtered and dried under a vacuum condition. Solutions for spray drying were prepared by dissolving 10 g of Mannitol into 190 g of distilled water with several % of PEG 4000 (0% to 10%) or organic solvents. All spray drying processes were performed by using a spray dryer, GS-31 (Yamato Scientific Co., Ltd.). The powder X-ray diffractometer Empyrean system (Spectris Co., Ltd., Panalytical B.V.), Differential scanning calorimeter DSC Q2000 (TA instruments), Scanning electron microscopy VE-7800 (Keyence Corporation) were used for evaluation of physical properties of samples.

Results and Discussions

Only β-mannitol was obtained by spray drying from mannitol aqueous solution without any other excipients. This result corresponded to the previous study by Littringer et al, although they reported that the processing conditions might not have an influence on the polymorphic state of mannitol, when highly concentrated mannitol solutions were spray dried, as β-mannitol was obtained in all case (14). Therefore, we tried to control the polymorphic state of mannitol and selectively produce α-mannitol by modifying the components of the solution for spray drying such as adding organic solvent or any other excipients.

Fig. 1 shows the powder X-ray diffraction (PXRD) patterns of mannitol spray dried from its aqueous solution including organic solvents, which were considered to allow the sprayed droplet drying process to be faster. The diffraction peaks of α-mannitol were observed in the PXRD patterns, however those of β- mannitol were also observed. Adding organic solvent was judged to be effective for controlling the polymorphic state of spray dried mannitol, however, its effect was not sufficient to selectively produce α- mannitol by spray drying.

Fig. 2 shows the PXRD patterns of mannitol co-spray dried with PEG 4000. PEG 4000 is the excipient which has already been used in commercial DPI formulations and is considered to have a reducing effect in the nucleation rate of mannitol during spray drying. According to the increase of PEG 4000 concentration, the diffraction peaks of β-mannitol had decreased and those of α-mannitol had increased as shown in Fig. 2. Above 1% of PEG 4000 concentration, the diffraction peaks originating from β-mannitol were completely eliminated and the PXRD pattern became the same as that of α-mannitol. From these results, adding PEG 4000 was also judged as effective to control the polymorphic state of spray dried mannitol. Furthermore, co-spray drying mannitol with above 1% of PEG 4000 was indicated to be able to produce α-mannitol selectively.

One of the possible reasons for the absence of β-mannitol in the sample spray dried from mannitol/the PEG 4000 system is considered due to the increasing viscosity of the sprayed droplets. The mobility of mannitol molecules in the presence of the PEG 4000 system during spray drying was reduced to that of mannitol alone. The transformation from α-mannitol nuclei into β-mannitol nuclei was inhibited according to the reduced molecular mobility. This hypothesis is substantiated by the fact that PEG 4000 has been shown to hydrogen bond with water (15), and it is reasonable to assume that the prevalence of such interactions in mannitol/PEG 4000/water systems reduce the molecular mobility and inhibit transformation from α-mannitol nuclei into β-mannitol nuclei.

○: β-mannitol ▼: α-mannitol

Fig. 1 Powder X-ray diffraction patterns of mannitol spray dried from its aqueous solution including organic solvent. The percentage of included organic solvents: a) 0%, b) 10% Ethanol, c) 25% Ethanol, d) 25% acetone, e) 50% acetone

○: β-mannitol ▼: α-mannitol

Fig. 2 Powder X-ray diffraction patterns of mannitol co-spray dried with PEG 4000. The concentration of PEG 4000: a) 0%, b) 0.2%, c) 0.5%, d) 1.0%, e) 10%

Conclusion

Adding not less than 1% of PEG 4000 into the solution for spray drying is found to be a useful method to selectively produce α-mannitol by spray drying, whereas, spray dried mannitol alone caused only β- mannitol. The mechanism by which only α-mannitol is provided in the presence of PEG 4000 during the spray drying is not yet completely understood, however, is likely to be related to the high affinity with which PEG 4000 hydrogen bonds with water, which can be expected to reduce the molecular mobility during the drying process. The controlling polymorphic state of mannitol and selectively producing α-mannitol by spray drying was successful by adding above 1% of PEG 4000.

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