Process analytical techniques for hot-melt extrusion and their application to amorphous solid dispersions.

Newly developed active pharmaceutical ingredients (APIs) are often poorly soluble in water. As a result the bioavailability of the API in the human body is reduced. One approach to overcome this restriction is the formulation of amorphous solid dispersions (ASDs), e.g., by hot-melt extrusion (HME). Thus, the poorly soluble crystalline form of the API is transferred into a more soluble amorphous form. To reach this aim in HME, the APIs are embedded in a polymer matrix. The resulting amorphous solid dispersions may contain small amounts of residual crystallinity and have the tendency to recrystallize. For the controlled release of the API in the final drug product the amount of crystallinity has to be known. This review assesses the available analytical methods that have been recently used for the characterization of ASDs and the quantification of crystalline API content. Well-established techniques like near- and mid-infrared spectroscopy (NIR and MIR, respectively), Raman spectroscopy, and emerging ones like UV/VIS, terahertz, and ultrasonic spectroscopy are considered in detail. Furthermore, their advantages and limitations are discussed with regard to general practical applicability as process analytical technology (PAT) tools in industrial manufacturing. The review focuses on spectroscopic methods which have been proven as most suitable for in-line and on-line process analytics. Further aspects are spectroscopic techniques that have been or could be integrated into an extruder.

Histones to the cytosol: exportin 7 is essential for normal terminal erythroid nuclear maturation.

Global nuclear condensation, culminating in enucleation during terminal erythropoiesis, is poorly understood. Proteomic examination of extruded erythroid nuclei from fetal liver revealed a striking depletion of most nuclear proteins, suggesting that nuclear protein export had occurred. Expression of the nuclear export protein, Exportin 7 (Xpo7), is highly erythroid-specific, induced during erythropoiesis, and abundant in very late erythroblasts. Knockdown of Xpo7 in primary mouse fetal liver erythroblasts resulted in severe inhibition of chromatin condensation and enucleation but otherwise had little effect on erythroid differentiation, including hemoglobin accumulation. Nuclei in Xpo7-knockdown cells were larger and less dense than normal and accumulated most nuclear proteins as measured by mass spectrometry. Strikingly,many DNA binding proteins such as histones H2A and H3 were found to have migrated into the cytoplasm of normal late erythroblasts prior to and during enucleation, but not in Xpo7-knockdown cells. Thus, terminal erythroid maturation involves migration of histones into the cytoplasm via a process likely facilitated by Xpo7.

From benchtop to pilot scale-experimental study and computational assessment of a hot-melt extrusion scale-up of a solid dispersion of dipyridamole and copovidone.

The aim of our work was to study and define a computationally-based adiabatic scale-up methodology for a hot-melt extrusion (HME) process to produce an amorphous solid dispersion (ASD). As a drug product becomes commercially viable, there is a need for scaling up the manufacturing process. In the case of HME used for the formation of ASDs, scale-up can be challenging due to the fundamental differences in how heat is generated in extruders of differing scale, i.e. conduction vs. viscous dissipation and the significant role heat generation plays in determining the final product attributes. Using a 30%w/w dipyridamole-in-copovidone formulation, 11 mm-, 16 mm- and 24 mm-diameter extruders with L/D 40, solid-state characterization tools, a geometric scaling equation, and Ludovic® twin-screw extrusion software, we compared the total imparted material energy, the conducted energy and the difference between barrel and melt temperature at die exit for various feed rates and screw speeds. Numerical simulation identified desirable adiabatic conditions at multiple extruder scales in agreement with the chosen scaling factor. With the use of computational tools, the energetics in an extrusion process can be evaluated and processing conditions can be selected to identify the most efficient scaling of a HME process.

Lubricating agents differ in their protection of cultured human epithelial cells against desiccation.

BACKGROUND: In dry eye, as a disease of the ocular surface, the instillation of artificial tears should compensate for the deficit in wetting and protect the mucosa against drying. MATERIAL/METHODS: The desiccation protection of different pharmacological substances was tested using the conjunctival epithelial cell line Chang 1-5c-4 (series 1) and the corneal cell line 2.040 pRSV-T (series 2). On confluent cell growth the cultures were wetted for 20 min with various preservative-free preparations of artificial tears The cell cultures were exposed to a constant air flow for 0, 15, 30 and 45 minutes. Cells were incubated with the vital dye Alamar Blue and subsequently absorption of the oxidised form of the dye was measured using an ELISA-Reader. RESULTS: Cell survival rates in series 1 after 0, 15, 30, 45 min were (1.02;0.81;0.35;0.32) for Artelac EDO, (0.82;0.69; 0.63;0.54) for Vidisic EDO, (0.77;0.80;0.67;0.70) for Vidisic Fluid EDO, (0.76;0.70;0.36; 0.34) for Acuolens, (0.97;0.46;0.35;0.33) for Viscofresh, (0.88;0.85;0.37; 0.33) for Hyal Drops SDU, (0.71;0.44;0.34;0.33) for PBS and in series 2 (1.03;0.84;-0.21;-0.20) for Artelac EDO, (0.89;0.92;0.93;0.86) for Vidisic EDO, (0.96;0.88;0.85;0.85) for Vidisic Fluid EDO, (1.01;0.75;-0.02;-0.03) for Acuolens, (0.98;0.17;-0.22;-0.20) for Viscofresh, (0.97;0.83;0.03;-0.21) for Hyal Drops SDU and (0.96;0.26;-0.24;-0.21) for PBS. Vidisic Fluid EDO and Vidisic EDO showed a significantly better protective effect after a drying period of 30 and 45 min. CONCLUSIONS: The protection capability of pharmacological substances against desiccation can be studied in a standardised cell culture system of human epithelial cell lines. Whether these in vitro results are conferrable to the efficacy of artificial tear drops in vivo has to be evaluated in clinical trials.