Continuous manufacturing of delta mannitol by cospray drying with PVP.

Mannitol is a frequently used diluent in the production of tablets due to its non-hygroscopic character and low drug interaction potential. Although the δ-polymorph of mannitol has superior tabletability in comparison to α- and ß-mannitol, the latter are most commonly used because large-scale production of δ-mannitol is difficult. Therefore, a continuous method for production of δ-mannitol was developed in the current study. Spray drying an aqueous solution of mannitol and PVP in a ratio of 4:1 resulted in formation of δ-mannitol. The tabletability of a physical mixture of spray dried δ-mannitol with PVP (5%) and paracetamol (75%) was clearly superior to the tabletability of physical mixtures consisting of spray dried α- and ß-mannitol with PVP (5%) and paracetamol (75%) which confirmed the excellent tableting properties of the δ-polymorph. In addition, a coprocessing method was applied to coat paracetamol crystals with δ-mannitol and PVP. The tabletability of the resulting coprocessed particles consisting of 5% PVP, 20% δ-mannitol and 75% paracetamol reached a maximal tensile strength of 2.1 MPa at a main compression pressure of 260 MPa. Moreover the friability of tablets compressed at 184 MPa was only 0.5%. This was attributed to the excellent compression properties of δ-mannitol and the coating of paracetamol crystals with δ-mannitol and PVP during coprocessing.

Fatty acids for controlled release applications: A comparison between prilling and solid lipid extrusion as manufacturing techniques.

The aim of the present study was to evaluate the solid state characteristics, drug release and stability of fatty acid-based formulations after processing via prilling and solid lipid extrusion. Myristic acid (MA), stearic acid (SA) and behenic acid (BA) were used as matrix formers combined with metoprolol tartrate (MPT) as model drug. The prilling process allowed complete dissolution of MPT in the molten fatty acid phase, generating semi-crystalline MPT and the formation of hydrogen bonds between drug and fatty acids in the solid prills. In contrast, as solid lipid extrusion (SLE) induced only limited melting of the fatty acids, molecular interaction with the drug was inhibited, yielding crystalline MPT. Although the addition of a low melting fatty acid allowed more MPT/fatty acid interaction during extrusion, crystalline MPT was detected after processing. Mathematical modeling revealed that the extrudates exhibited a higher apparent drug/water mobility than prills of the same composition, probably due to differences in the inner systems' structure. Irrespective of the processing method, mixed fatty acid systems (e.g. MA/BA) exhibited a lower matrix porosity, resulting in a slower drug release rate. Solid state analysis of these systems indicated that the crystalline structure of the fatty acids was maintained after SLE, while prilling generated a reduced MA crystallinity. Binary MPT/fatty acid systems processed via extrusion showed better stability during storage at 40 °C than the corresponding prills. Although mixed fatty acid systems were stable at 25 °C, stability problems were encountered during storage at 40 °C: a faster release was obtained from the prills, whereas drug release from the extrudates was slower.

Enteric protection of naproxen in a fixed-dose combination product produced by hot-melt co-extrusion.

In this study hot-melt co-extrusion is used as processing technique to manufacture a fixed-dose combination product providing enteric protection to naproxen incorporated in the core and immediate release to esomeprazole magnesium embedded in the coat. The plasticizing effect of naproxen and triethyl citrate (TEC) was tested on the enteric polymers investigated (Eudragit(®) L100-55, HPMC-AS-LF and HPMCP-HP-50). Core matrix formulations containing HPMC-AS-LF, TEC and a naproxen load of 15, 30 and 50% were processed and characterized. The in vitro naproxen release in 0.1N HCl was prevented for 2h for all formulations. The physicochemical state of the drug in the extrudates was determined and a stability study was performed. Intermolecular interactions between naproxen and polymer were identified using attenuated total reflection Fourier-transform infrared (ATR FT-IR) spectroscopy. When esomeprazole magnesium was formulated in a polyethylene oxide 100K:polyethylene glycol 4K (1:1) matrix, separated from the naproxen-containing layer, the formulation could be easily processed and complete in vitro drug release was observed after 45 min. When co-extruding the core/coat dosage form it was observed that a third layer of polymer, separating the naproxen loaded enteric formulation in the core from the coat, is required to prevent degradation of the acid-labile esomeprazole magnesium at the core/coat interface.

Prilling as manufacturing technique for multiparticulate lipid/PEG fixed-dose combinations.

This study focused on the evaluation of prilling as a technique for the manufacturing of multiparticulate dosage forms. Prills, providing controlled and immediate drug release, were processed and finally combined in capsules yielding a fixed-dose combination. Metoprolol tartrate (MPT) and hydrochlorothiazide (HCT) were used as controlled and immediate release model drugs, respectively. These drugs were embedded in matrices composed of fatty acids and polyethylene glycol (PEG). In order to tailor drug release from the prills, the type of fatty acid, the PEG molecular weight and the fatty acid/PEG ratio were varied. To provide controlled drug release, MPT was embedded in matrices containing PEG and behenic acid. Using different PEG molecular weights (PEG 4000, 6000 and 10,000), MPT release could be tailored over a wide range. To obtain immediate release, HCT was incorporated in matrices composed of PEG and stearic acid. Since high amounts (at least 60%) of PEG were needed for acceptable immediate release, HCT release was independent on PEG molecular weight. Solid state characterization revealed that MPT crystallinity was decreased, while HCT was molecularly dispersed throughout the matrix. Drug release of both MPT and HCT prills was stable during storage. Compared to a fixed-dose reference, oral co-administration of the MPT and HCT prills to dogs yielded a similar bioavailability for the HCT prills, while the MPT prills resulted in a significant higher bioavailability.

Co-extruded solid solutions as immediate release fixed-dose combinations.

The aim of this study was to develop by means of co-extrusion a multilayer fixed-dose combination solid dosage form for oral application characterized by immediate release for both layers, the layers containing different drugs with different water-solubility. In this study polymers were selected which can be combined in a co-extruded dosage form. Several polymers were screened on the basis of their processability via hot-melt extrusion, macroscopic properties, acetylsalicylic acid (ASA) decomposition and in vitro drug release. ASA and fenofibrate (FF) were incorporated as hydrophilic and hydrophobic model drugs, respectively. Based on the polymer screening experiments Kollidon® PF 12 and Kollidon® VA 64 were identified as useful ASA carriers (core), while Soluplus®, Kollidon® VA 64 and Kollidon® 30 were applicable as FF carriers (coat). The combination of Kollidon® 30 (coat) with Kollidon® PF 12 or Kollidon® VA 64 (core) failed in terms of processability via co-extrusion. All other combinations (containing 20% ASA in the core and 20% FF in the coat) were successfully co-extruded (diameter core: 2mm/thickness coat: 1mm). All formulations showed good adhesion between core and coat. ASA release from the core was complete within 15-30 min (Kollidon® PF 12) or 30-60 min (Kollidon® VA 64), while FF release was complete within 20-30 min (Kollidon® VA 64) or 60 min (Soluplus®). Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) revealed that both drugs were molecularly dispersed in the carriers. Raman mapping exposed very little intermigration of both drugs at the interface. Fixed-dose combinations with good in vitro performance were successfully developed by means of co-extrusion, both layers providing immediate release.