Effect of different molecular weights of polyethylene glycol as a plasticizer on the formulation of dry powder inhaler capsules: Investigation of puncturing size, morphologies, and surface properties

2.1 Materials

All of the starting materials were used as received from valid companies without further purification. Gelatin type B was received from Henan Boom Gelatin Co. (China) and Lapi Gelatin Spa (Italy). Methylparaben and Propyl paraben were acquired from UENO Fine Chemical Industry (Japan), Sodium lauryl sulfate (SLS) was obtained from Godrej Industry (India). Polyethylene Glycol 400 (PEG 400) and Propylene glycol (PG) were purchased from Kimyagaran Emrooz Chemical Industries Co. (Iran), Colloidal Nano silicon dioxide (SiO₂) was achieved from Evonik (Germany), Acetic acid glacial, and Zinc sulfate heptahydrate (ZnSO₄·7H₂O) were obtained from Dr. Mojallali Industrial Chemical Complex Co. (Iran) and Behansar (Iran), respectively.

2.2 Production procedure

2.3 Equipment's

The equipment and devices used in this research work include a homemade feed tank (160 Lit), mechanical stirrer with propeller blade, Brookfield Viscosel (VTE model, USA), manufacturing machine (size 3, HGCM, 03–06 380 V, 200Amps, 50 Hz, SCR 10KA, Technophar, Canada), quality control gauges (VSX136, Mitutoyo Japan), fan dryer (GB-121–3, GREENHECK Technophar, Canada), sorting machine (CI5S, Suzhou Sunny Pharmaceutical Machinery Co. ltd.), and hygrometer (MA35M-230 N, Sartorius Lab Instrument, Germany). The scanning electron microscopy (SEM) was recorded on a VEGA TESCAN to investigate the morphology and size of the as-prepared capsules and their puncturing holes diameter. The AFM device was the Ara Research Co Nano Experts model. All of the AFM investigations were performed in the tapping mode at room temperature. The capsule surfaces were measured in a scan size of 5 μm × 5 μm. The surface roughness parameters of the capsules, which are reflected in terms of the mean roughness (Sa), the root mean square of the Z data (Sq), and the mean difference between the highest peaks and lowest valleys (Sz) was achieved by Ara Research Co Nano Experts software for quantitating analysis of images.

3.1 Optimizing plasticizer on laboratory scale

It is noteworthy that an ideal plasticizer should possess a series of beneficial parameters such as polarity, size, availability of polar groups, and shape of plasticizer. Table 1 depicts the formulation of samples F1 to F12 containing different plasticizers. As can be seen in this table, the effect of each plasticizer was studied to evaluate the brittleness of gelatin films. Various plasticizers, including Gly, PG, PEG-400, PEG-600, PEG-1500, and PEG-4000, were evaluated to select the suitable plasticizer for the formulation of DPI capsules. These materials were prepared as a film by combining different percentages (samples F1 to F12), and their brittleness was evaluated after 2.0 and 24.0 h of drying (Fig. 1). The results showed that the film containing Gly became very brittle and was highly susceptible to particle formation. This is because of the interaction type of Gly and gelatin that makes its structure hard and brittle. In other words, Gly changed the absorption features of gelatin films, increasing the amount of water at high relative humidities and reducing it at low relative humidities, proposing complicated polyol-matrix interactions (Díaz et al., 2011). Besides, the existence of PG reduces the tensile strength and elastic stiffness of the capsule, making it more brittle and weaker (Mei et al., 2006).

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Fig. 1

A schematic demonstration of (a) PEG molecular structure and investigating the effect of PEG on plasticizing of gelatin film (a) as-prepared samples (b) after drying (2.0 h) and (c) after drying (24.0 h).

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The results showed that plasticizers containing hydroxyl functional groups demonstrate promising potential for protein-based materials because of their capability to decrease intermolecular hydrogen bonding whenever enhancing intermolecular spacing. Therefore, PEGs with various molecular weights, including 400, 600, 1500, and 4000 in four particular weight percentages, were added to the gelatin capsule formulation (Table 1). Plasticized gelatin films made of PEG with various molecular weights change in appearance. It was found that plasticizers tended to migrate to film surfaces for films plasticized by PEG that had a molecular weight of more than 1500. As a result, the films made of PEG1500 and PEG4000 had an opaque surface. However, films plasticized by PEG400 and 600 were transparent. The results revealed that the higher molecular weights of PEG were not a convenient choice for further considerations in DPI capsule formulation since the solution became two-phase with unfavorable parameters. According to the obtained results, the molecular weight of 400 exhibits an effectual effect during the capsule manufacturing process, in which its changes follow an exponential function. The outcome of these manual pining was approximately 80 DPI capsules. The results of these assessments illustrate that an increase in the PEG400 content in the gelatin formulation leads to a delay in the drying process. The capsules with 20 %wt PEG400 did not dry at a certain time. Drying of capsules with 15 %wt PEG400 was possible with a 50-minute delay, which is neither economically practical nor economical. Production of capsules with 10 %wt PEG400 was possible. Hence, this value (10 %wt PEG400) was selected and approved as the optimal amount of PEG400 and this percentage is optimized for industrial production (Fig. 2).

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Fig. 2

The effect of PEG400 content on different punching times in optimum formulation (n = 3).

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3.2 Producing DPI capsules on an industrial scale

Based on previous knowledge, the parameters of the manufacturing machine must be fundamentally changed to produce DPI capsules (size 3) with a new melting formulation containing 10 %wt PEG400. Changing the speed of the air conditioners is essential to increase the capacity of the machine for manufacturing DPI capsules. Adjusting these parameters was necessary but not enough for complete drying. Therefore, several parameters were changed according to Table 3.

DPI capsules size 3 were produced by changing the parameters of the machine and the gelatin solution. 2 million capsules were manufactured on an industrial scale and were evaluated by the quality control unit. Several parameters, including the size, walls, domes, and shoulders of the prepared capsules, were reported. Concerning physical parameters, it is found that these manufactured capsules are in good agreement with standard capsule range parameters. Indeed, dimensional and physical appraisement of capsule parameters indicates that the manufactured capsules are within the global standard ranges (Fig. 3 and Table 4).

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Fig. 3

Normal graph distribution of produced DPI capsules (size 3).

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3.3 Comparing produced DPI capsules with commercial DPI capsules

The DPI capsules based on Gelatin/PEG400 that produced on an industrial scale in the gelatin capsule company (Iran) were compared with other commercial DPI capsules (HPMC and pure gelatin) available on the market. The results indicate (Fig. 4a) that gelatin/PEG-based DPI capsules lose some of their initial water content during the packaging process, but the moisture content stabilizes after 12.0 h. Due to the PEG used and its structure, this residual moisture prevents the capsule from becoming brittle.

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Fig. 4

a) Moisture content in manufactured capsules in different steps, and b) loss on drying (%) of Gelatin, Gelatin/PEG and HPMC capsules in different intervals (n = 3).

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Given that one of the essential and crucial parameters in capsules is moisture content. Loss on drying (LOD) of gelatin/PEG-based DPI capsules, pure gelatin, and HPMC capsules was evaluated and compared during 12.0 h (Fig. 4b). The results revealed that pure gelatin capsules have a higher moisture content than HPMC and gelatin/PEG capsules. Gelatin/PEG capsules have lower moisture than pure gelatin. The active pharmaceutical ingredient (API) must not aggregate and maintain its fine structure in the inhalation process. Therefore, it is better to use empty hard capsules with less moisture to fill these APIs. On the other hand, the lower moisture content can effectively prevent the API from reacting with the capsule shells. Although HPMC capsules have the most suitable moisture, since the machinery and equipment required for these capsules are cost-effective and not available in all countries, gelatin/PEG capsules are not only adequate in terms of moisture but also economically attainable.

Another important parameter of DPI capsules is the lack of particles in DPI capsules during the punching process. The rougher the surface of the capsule, the more particles are formed. Therefore, AFM analysis was used to evaluate and compare the roughness of pure gelatin, HPMC, and gelatin/PEG capsules. Fig. 5 shows 2D AFM photographs of gelatin (Fig. 5(a-c)), gelatin/PEG (Fig. 5(d-f)), and HPMC (Fig. 5(g-i)) capsules. The scan size of the images was 5 µm × 5 µm. The roughness parameters are shown in Table 5 based on the AFM image. The average roughness (S_a) of the capsules was estimated at 5, 2.5, and 7.5 µm for the gelatin, gelatin/PEG, and HPMC types, respectively. Indeed, when S_a is lower, the surface will be more uniform. It is noteworthy that the surface of the gelatin capsule has more roughness than the gelatin/PEG capsules and DPI capsules based on pure gelatin are prone to particle formation and brittleness.

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Fig. 5

2D AFM surface plots of (a-c) gelatin (d-f) gelatin/PEG and (g-i) HPMC capsules.

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In more detail, 3D AFM images of samples are illustrated in Fig. 6. As observed in Fig. 6, topographic images and roughness of the surfaces of the capsule samples can be seen with greater clarity and quality along different axes. It is worth noting that gelatin capsules with a rougher surface can have a greater potential for destruction (Fig. 6(a-c)). The higher roughness, the more brittleness the capsule. As a consequence, the utilization of PEG400 in capsule formulation diminishes the roughness or enhances the flexibility of the capsule against shrinkage and possible deformations (Fig. 6(d-f)). In fact, the flexibility of the manufactured capsule shells is remarkably enhanced due to the intermolecular interaction of gelatin with PEG400 (Scheme 1). The presence of plasticizing agent makes the gelatin chain very flexible and decreases related brittleness. Additionally, the presence of a plasticizing agent ensures that the capsule particles do not separate during punching.

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Fig. 6

3D AFM images of (a-c) gelatin, (d-f) gelatin/PEG, and (g-i) HPMC capsules in tapping mode.

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Scheme 1

A schematic illustration of the intermolecular interaction of PEG with gelatin chains.

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Given that the result of the punching process of DPI capsules is different from pure gelatin, HPMC, and gelatin/PEG (Scheme 2), the issue of not re-blocking the punched portion of the DPI capsule is another parameter to consider when developing DPI capsules. Therefore, SEM analysis was performed to evaluate this feature and determine the morphology and size of the punched part of DPI capsules. As observed in Fig. 7, the holes on the outer surfaces of capsules were monitored. The release of particles from the capsule into the API was identified from the SEM images of the gelatin capsule (Fig. 7a and 7b). In other words, due to punching, a negligible part of the capsule is inhaled with the drug and enters the patient's body. In more detail, the holes are circular in shape with a diameter of 2.19 mm. The SEM images of the gelatin/PEG capsule in Fig. 7c and 7d clearly show that no piece of the capsule is detached from its main body. Significantly, the addition of PEG400 to the DPI capsule formulation at a specific weight percentage gives the capsule the desired flexibility and does not release any particles easily. As shown in Fig. 7c and 7d, the addition of PEG400 to gelatin makes the properties and punching angle closer or quite similar to HPMC capsules. Conclusively, SEM results confirm that PEG400 is remarkably convenient and favorable for manufacturing DPI capsules. By comparing the SEM images of gelatin and gelatin/PEG, it is found that HPMC capsule holes are closer to gelatin/PEG capsules and smaller in size (1.84 mm) with no detached pieces (Fig. 7e and 7f), and the holes remained in regular shape.

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Scheme 2

A schematic representation for the puncturing process of gelatin, gelatin/PEG and HPMC capsules and obtaining SEM images.

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Fig. 7

SEM images from outside of prepared Gelatin capsule (a,b), gelatin/PEG capsule (c,d) and HPMC capsules (e,f).

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Furthermore, SEM techniques were taken from the inner surface of prepared capsules to figure out and address the internal surface characteristics, the size of the generated holes during punching, uniformity, and order of the holes. According to Fig. 8, it is evident that the gelatin capsule holes are not uniform in size. The size of the punched holes in the gelatin capsule was 1.76 mm. Fig. 8 displays the SEM images of the gelatin/PEG capsule inner surface. It is observed that the presence of PEG enhances the plasticity of this kind of capsule. This type of capsule does not show any particle release. It is conceivable that this behavior is due to the presence of PEG in capsule formulation and its plasticizing function.

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Fig. 8

SEM images from inside of prepared gelatin/PEG capsule (a,b), Gelatin capsule (c,d) and HPMC capsules (e,f).

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