Extrusion processing was optimized to obtain the extrudates as yellowish pellets of 1 mm length of granules by feeding the pellets in a cutter mill (Fig. 1). The temperature profiles, screw speed and the feed rate were found to be the critical processing parameters (CPP) for the development of the extruded pellets or granules. During the optimisation of the process to manufacture INM controlled release formulations, a range of temperature profiles from 120 to 140°C were evaluated and subsequently processing conditions and outputs such as shear force, torque, feed rate and screw speed were optimized.
By keeping the final processing condition and the throughput of the drug/polymer/lipid powder blends, final batches of formulations were extruded as shown in Table I with a feed rate of 1 kg/h and a screw speed of 50–150 rpm. All conveyed extruded strands via a compressed air conveyor belt facilitated the feeding of the extrudates to the pelletizer attached at the end of the conveyor. The pelletizer resulted in the production of the pellets with 1 mm length. The length of the pellets was homogenously cut into pieces by pelletizer as the speed and processing conditions were adjusted.
All formulations were easily extruded to produce strands with INM loadings varying from 20 to 40% (w/w ratio). All materials were found to be miscible according to the Hansen solubility parameters (δ2) (25,26). The estimated solubility values of INM (22.8 MPa1/2), HPMCAS (25.30 MPa1/2) and GLC (19.8 MPa1/2) showed a difference of Δδ < 7.0 MPa1/2 suggesting complete miscibility with each other (Supp. Table 1). Although INM presents a high melting point, the polymer/lipid formulations were extruded at relative low temperatures due to the addition of the lipid, which acted as a plasticizer. However, as it can be seen in Table I, due to the requirements for increased drug loadings (30–40%) and high throughput (1 kg/h), the extrusion temperature profiles were adjusted to higher temperatures. The reason for these changes was to improve formulation processability and prevent the creation high torque in the extrusion barrels.
Surface morphology was examined by SEM for both the drug/polymer/lipid physical mixtures and the extrudates (EXT). As can be seen in Fig. 2a–c, the drug crystals appeared to be irregular in shape (needle type) and size. The physical mixture of the drug and carrier (lipid/polymer) showed the presence of drug in the crystalline form, which is distinguishable from the HME granules. In case of extrudates (Fig. 2d–f), it was difficult to distinguish the presence of drug crystals. This could be due to the presence of amorphous INM onto the lipid/polymeric matrices during the extrusion processing (more details in the DSC and XRD sections). Furthermore, the sieving analysis (data not shown) after the optimized micronisation of the pellets presented particle sizes lower than 500 μm for all extruded formulations ranging from 40 to 250 μm.
Differential scanning calorimetry (DSC) was used to determine the solid state of the drug in the extruded matrices as well as to outline any possible intermolecular drug-lipid-polymer interactions. Figure 3 shows the thermal transitions of pure INM, GLC and HMPCAS. The bulk INM showed an endothermic thermal transition at 161.18°C (ΔH = 115.33 j/g), which corresponds to its melting peak while GLC exhibited an endothermic sharp melting peak at 45.32°C (ΔH = 143.67°C). Similarly, the bulk HMPCAS pure showed a step change due to glass transition temperature at 128.21°C. The DSC analysis (Fig. 3) of the extruded F1-F2 formulations showed a shift of the HMPC glass transition at lower temperatures at 86.14 and 88.31°C, respectively, while the INM melting endotherm disappeared from the 161°C compare to the bulk substance. These results indicate the existence of INM amorphous state within the extruded matrices (1), and it is attributed to the possible drug-lipid-polymer intermolecular interactions during the extrusions. The same composition (F3) was processed at high screw rates and extrusion temperatures, and IND was also found in amorphous state (data not shown). However, different thermal events were recorded for the other extruded formulations (F4-F6) as shown in Table II. These formulations revealed melting endotherms due to the presence of crystalline drug in the extruded formulations (data not shown). In addition, the binary physical mixture (F6) showed a melting endotherm due to the presence of crystalline INM at 135.84°C (ΔH = 17.85°C). In contrast, the extrudates revealed two endothermic thermal events at 71.46°C corresponding to the melting of crystalline drug and another one at relatively higher temperature at 145.91°C due to the Tg of the amorphous polymer (Supp. Fig.1) indicating the existence of crystalline INM in the system.
Hot stage microscopy (HSM) studies were conducted to visually determine the thermal transitions and the extent of drug melting within the polymer/lipid matrices at different stages of heating. Images taken using HSM under optical light are shown in Fig. 4. The bulk INM showed no changes up to 150–160°C, which is in agreement with the DSC results as thermal transition due to the melting of the drug occurred at 161°C. Similarly to the DSC thermograms, the INM/HMPC/GLC extrudates (F2) showed nominal API solubilization into the hydrophilic molten polymer/lipidic matrices up to 100–120°C and thereafter showed complete solubilization of the drug (Fig. 4). This could potentially be attributed to the intermolecular interactions or possibly the solubilization of the drug into polymer/lipid matrices during the extrusion processing.
X-Ray Powder Diffraction Analysis
The drug-polymer-lipid extrudates, including the bulk drug and physical mixtures of the same composition, were studied by X-ray analysis, and the diffractograms were recorded to examine the crystalline state of INM. As can be seen from Fig. 5a, the diffractogram of pure INM (average particle size below 100 μm) showed distinct intensity peaks at 10.17°, 11.62°, 17.02°, 19.60°, 21.82°, 23.99°, 26.61°, 29.37°, 30.32°, 33.55° degree 2θ. The physical mixtures of INM formulation showed identical peaks at lower intensities suggesting that the drug retained its crystallinity. In contrast, no distinct intense peaks due to INM were observed in the diffractograms of the extruded F1-F3 formulations. The absence of INM intensity peaks indicates the presence of amorphous INM into the polymer/lipid matrix complementing the findings from DSC. However, INM/HMPCAS (binary) extruded formulation (F6) revealed distinct intensity peaks of the drug at 12–17° 2θ and 22–27° 2θ values (Fig. 5b), simply indicates the presence of crystalline drug in the extruded formulation. Some additional XRD results of F4-F6 extruded formulations are provided in supplementary documents (Supp. Fig. 1a–d). All additional formulations showed characteristic peaks of the crystalline INM at relatively lower intensity which indicates the presence of crystalline drug in the extruded formulations. This could be due the averse or incomplete mixing during the extrusion processing while the presence of the lipid as third excipient has facilitated the homogenous mixing and thus the interactions. Hence, the presence of the lipidic carrier facilitated the formation of amorphous solid dispersions with high drug loading.
In-Line Near-Infrared Spectroscopy
In a continuous manufacturing system of any dosage forms, it is paramount to control and monitor quality attributes of the processed materials for enhanced product performance. In order to monitor critical quality attributes of the drug within the hydrophilic polymeric/lipidic matrices, a near-infrared (NIR) fibre probe was used as process analytical technology (PAT) tool and all the in-line data generated during the process were collected using the appropriate software package. NIR spectra of INM, HMPCAS, GLC pure were measured off-line to determine the characteristic vibrational bands attributable to the chemical structures of the bulk substance (Fig. 6a). Subsequently, in-line NIR spectra of the INM/HMPCAS/GLC extruded formulations were collected from different mixing zones during extrusion processing. The second derivative spectra, in Fig. 6b, shows a significant band shift between the NIR spectrum of bulk INM and the extruded formulations. The peak shifts at 4664, 5789, 6006 cm−1 are mainly due to the interactions between INM and the carriers. In addition, the increased peak intensity suggests the formation of strong intermolecular interactions. Interestingly, a new peak at 2549 cm-1, which does not exist in the bulk materials and the physical mixture, appeared in the extruded formulations. This peak corresponds to second overtone of the C = O stretching mode of the C–H···O = C hydrogen bonding between INM and probably HPMCAS. It is obvious that the second derivative peaks exhibited a frequency shift towards higher wave numbers compared to that of bulk substances. These changes in the spectrum could be attributed to the interaction (e.g. hydrogen bonding) (27) involved in the solid dispersion formation between the drug and carriers.
In vitro Dissolution Study
The dissolution behaviour of the processed formulations was assessed for extruded granules (average particle size 250 μm) and pellets (1 mm) in comparison to the bulk INM powder. As shown if Fig. 7 (and Supp. Fig. 3), a lag time with no drug release was observed for 2 h in acidic dissolution media for all of the extruded formulations. It appears that the polymer has a predominant effect and prevents drug release at low pH values. At higher pH values, INM was rapidly released within 1 h. The lag time was attributed to the pH dependency of HMPCAS, which dissolves at higher pH 5.5 (28).
Interestingly, HMPCAS/GLC showed a synergistic effect resulting INM release in faster rates compared to those of INM/HMPC extrudates. It can be clearly seen that extruded polymer/lipid formulations affected significantly INM dissolution rates (Fig. 7). The synergistic effect of GLC/HMPCAS revealed a release of about 90% in 30 min while for HMPCAS/INM (F6), only 20% was released after 3 h in basic media. There was no significant difference observed between the extruded pellets and granules of F1-F3 investigated by calculating the similarity factor (f2). According to the FDA guidelines, release curves are considered similar when the calculated f2 is 50–100 (29).
However, the other extruded formulations F4-F6 showed relatively low drug release due to the presence of higher INM crystalline content in the extrudates (Supp. Fig 3). A careful look in the release profiles of these formulations indicates that high drug loadings screw speeds are critical parameters and facilitate increased IND crystalline content in the extrudates.