Evidence of transient amorphization during the polymorphic transformation of sorbitol induced by milling

International audienceIn this paper, we show that the polymorphic transformation → of sorbitol upon milling involves a transient amorphization of the material. This could be done by comilling sorbitol with a high Tg amorphous material (Hydrochlorothiazide, Tg = 115°C) to stabilize any transient amorphous fractions of sorbitol through the formation of a molecular alloy. The results indicate that for large sorbitol concentration (50%), the comilling leads to a heterogeneous mixture made of sorbitol crystallites in the form embedded into an amorphous molecular alloy sorbitol / HCT. Interestingly, the kinetic investigation of this transformation reveals that these two components are not produced simultaneously. On the contrary, they are produced one after the other, during two distinct consecutive stages. The first stage concerns the formation of the amorphous alloy while the second one concerns the polymorphic transformation → of the fraction of crystalline sorbitol not involved in the alloy. These results clearly indicate that the polymorphic transformation of sorbitol upon milling results from the recrystallization of a transient amorphous state generated by the mechanical shocks. The investigations were mainly performed by calorimetry and powder X-ray diffraction

Towards a better understanding of the release mechanisms of caffeine from PLGA microparticles

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PEO hot melt extrudates for controlled drug delivery: Importance of the type of drug and loading

International audienceA variety of poly(ethylene oxide) (PEO)-based matrix tablets loaded with theophylline, ibuprofen or metoprolol tartrate was prepared via hot melt extrusion. The initial drug loading was varied from 10 to 60 %, the PEO polymer molecular weight from 300 to 7,000 kDa. The extrudates were characterized before and after exposure to phosphate buffer pH 7.4 at 37 °C using optical and scanning electron microscopy, X-ray diffraction analysis and drug release measurements. In the case of metoprolol tartrate, the resulting drug release rates monotonically increased with increasing initial drug loading, irrespective of the PEO grade. This can be attributed to an “increased porosity effect” upon drug leaching, resulting in less hindrance for subsequent drug release. However, in the case of theophylline and ibuprofen, also “limited drug solubility effects” played a role and were even dominant in 7,000 kDa PEO-based extrudates: Upon water penetration into the system, not all of the drug was dissolved. Dissolved and non-dissolved drug co-existed. Importantly, only dissolved drug is available for diffusion. Thus, increasing the initial drug content did not increase the concentration gradients of dissolved drug (and the absolute drug release rates in the absence of porosity effects), but increased the 100 % reference values. Interestingly, in 300 kDa PEO-based extrudates, “increased porosity effects” dominated for all drugs, and the relative release rates always increased with increasing drug loading. At 1,000 and 7,000 kDa, the resulting released rate increased or decreased with increasing drug loading, depending of the type of drug

Using Milling to Explore Physical States: The Amorphous and Polymorphic Forms of Sulindac

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Hot melt extruded polysaccharide blends for controlled drug delivery

International audienceDifferent types of hot melt extrudates were prepared based on a variety of blends of ethylcellulose with a 2nd polysaccharide, namely hydroxypropyl methylcellulose (HPMC), pectin, maize starch, inulin, maltodextrin, guar gum, and chitosan. In selected cases, the polymer:polymer blend ratio was varied from 80:20, 70:30, 60:40, 50:50, 40:60, 30:70 to 20:80. The addition of appropriate amounts of plasticizers allowed reducing the extrusion temperature to about 100 °C. The impacts of the screw speed, extrusion temperature, amount and type of plasticizer as well as of the amount and type of drug (10–60% theophylline or diprophylline) were studied. Drug release was measured in 0.1 M HCl for 2 h, followed by phosphate buffer pH 6.8 and (optionally) fecal samples to simulate the colon (under anaerobic conditions). DSC measurements and optical microscopy were used to characterize the physical state and morphology of the systems. Interestingly, hot melt extrudates based on ethylcellulose:guar gum blends could be easily prepared at a temperature of 100 °C and offered large spectra of drug release patterns for both: slightly water-soluble theophylline as well as freely water-soluble diprophylline. About constant drug release rates could be obtained during prolonged periods of time. Importantly, the resulting drug release rates from hot melt extrudates based on ethylcellulose:guar gum 80:20 blends were similar in the presence and absence of colonic bacteria, indicating that the ethylcellulose seems to protect the guar gum from degradation upon exposure to fecal samples. Furthermore, these systems were long term stable for at least 1 year under ambient conditions. Thus, they can offer an interesting potential as oral controlled drug delivery systems

Injection-molded capsule bodies and caps based on polymer blends for controlled drug delivery

International audienceA variety of polymer:polymer blends was used to prepare hot melt extrudates and empty capsules (bodies and caps) by injection-molding using a benchtop extruder (Babyplast). Kollidon SR:inulin and Carbothane:inulin blends were investigated. The impact of the blend ratio on the water uptake and dry mass loss kinetics upon exposure to 0.1 M HCl, phosphate buffer pH 6.8 and culture medium optionally inoculated with fecal samples from Inflammatory Bowel Disease (IBD) patients were studied. Hot melt extrudates were loaded with up to 60 % theophylline, capsules were filled with drug powder. Increasing the inulin content led to increased water uptake and dry mass loss rates, resulting in accelerated drug release from the dosage forms, irrespective of the type of polymer blend. This can be attributed to the higher hydrophilicity/water-solubility of this polymer compared to Kollidon SR and Carbothane. Interestingly, the presence of fecal samples in culture medium increased the water uptake and dry mass loss of hot melt extrudates to a certain extent, suggesting partial system degradation by bacterial enzymes. However, these phenomena did not translate into any noteworthy impact of the presence of colonic bacteria on theophylline release from the investigated extrudates or capsules. Hence, drug release can be expected to be independent of the location “small intestine vs. colon” from these dosage forms, which can be advantageous for long term release throughout the entire gastro intestinal tract

Thinking of bosentan repurposing – A study on dehydration and amorphization

International audienceNew clinical indications for an orphan drug bosentan are prompting the improvement of the drug formulation. Since bosentan is available as monohydrate, the information on its anhydrous form together with the assessment of its glass forming ability is necessary when developing enabling formulations. The aim of this research was, therefore, to analyze the phenomena occurring upon dehydration and amorphization of bosentan. The anhydrous form was obtained by a thermal treatment of the monohydrate and characterized for the first time using DSC and XRD. Two stable amorphous forms were prepared by cooling of the melt and high energy ball milling (Tg = 82 ⁰C). The chemical stability of milled bosentan was evaluated using ATR-IR and 1H NMR as well. The kinetics of bosentan amorphization was established. It was stated that bosentan could be easily amorphized. Importantly, even if the system was semiamorphous, there was no recrystallization while heating. The concentration–time curves recorded in biorelevant media, confirmed the beneficial effect of amorphization on the dissolution of bosentan. Yet, the amorphous form recrystallized into the monohydrate form in the gastric milieu. This phenomenon was accompanied by a reversible color change from yellow, which is typical of bosentan glass, to creamywhite that is characteristic of the crude crystalline dru

The technological solutions to enhance the bioavailability of tadalafil

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