Physical instability arguably is the major challenge in using neat amorphous active pharmaceutical ingredients in everyday tablets and capsules . The conversion of an amorphous form to the crystalline state either during storage or drug dissolution constitutes physical instability of amorphous drugs, and it impedes the solubility advantages that they provide. To elucidate the mechanisms behind physical instability, we have recently studied the relaxations of amorphous drug molecules and confirmed that amorphous drugs, like most amorphous materials, do have a secondary relaxation, the so-called β-relaxation [2, 3]. This relaxation dictates the mobility of the drug molecules when stored below their primary glass transition temperature, and amorphous drugs become physically stable when stored below the β-relaxation temperature . This temperature, however, can be very low, and thus makes stabilization of neat amorphous drugs practically difficult in most cases . Based on the fundamental β-relaxation phenomenon underpinning physical instability, it is obvious neat amorphous drugs need to be stabilized, using e.g. polymers, coamorphization, or porous materials, for practical pharmaceutical use. Stabilization of amorphous drugs using polymeric glass solutions (also called amorphous solid dispersions) is more often attempted, and usually based on the thermodynamic solubility of the drug in the polymer . Stabilization using coamorphization is an alternative to the use of polymers and is based on interactions between drug and low molecular weight excipient molecules and thus a hindrance to molecular mobility [5, 6]. Porous inorganic materials, however, can also stabilize amorphous drugs by interaction and spatial confinement [7, 8].
It is generally assumed that it is advantageous if the excipient remains amorphous to avoid inducing recrystallization of the drug. However, we found that for mesoporous silica amorphous drug formulations, hydrogen bonding between the interacting functional group and the silica surface forms strong hydrogen bonding similar to those found in their respective crystalline drug . This is interesting since it shows that the excipient intended for stabilization does not necessarily need to be amorphous and widens the scope of materials that can be used for stabilization. In an attempt to find new materials for stabilization of amorphous drugs, we have investigated the amorphization, physical stability and in vitro drug release of the model drug carvedilol when co-milled with functionalised calcium carbonate (Omyapharm® 500-OG).
For amorphization kinetics, the starting materials functionalised calcium carbonate (FCC) and carvedilol (CAR), and physical mixtures of 50% (w/w) of CAR and FCC (50% CAR) were milled for 90 min. Sampling was performed at 10, 20, 30, 60 and 90 min of milling and the samples were subjected to X-ray powder diffraction analysis (XRPD). The diffractogram of FCC showed no peaks at the low angle (5-22° (2θ)) however, crystalline peaks are present at high angles, and after 90 min of milling the crystalline peaks are still present. In contrast, carvedilol required between 10-20 min of milling to become amorphous.
For the physical mixture containing 50% CAR, it was observed that CAR crystalline peaks were absent already after 10 min of milling while FCC crystalline peaks are still visible, even after 90 min of milling (Fig. 1). This indicates that co-milling of FCC and CAR improves the amorphization kinetics of the drug.
To investigate the physical stability of the co-milled samples, different drug ratios, 10-80% CAR, were again prepared by milling for 30 min and analysed by DSC and XRPD. The DSC analysis of the mixtures at various drug ratios showed a glass transition temperature at 38 °C, which is similar to that of amorphous CAR (Fig. 2). It was observed that drug ratios from 30% CAR and below did not show a melting endotherm indicating that at stress conditions, 10-30% drug can be stabilized in the CAR-FCC mixtures. Under dry storage conditions at room temperature, it was observed that CAR-FCC samples containing 50-60% CAR recrystallized within a week, samples containing 40% CAR recrystallized after 11 weeks, and samples containing 10-30% CAR were stable for the testing period of 40 weeks.
Figure 1: XRPD diffractograms of CAR-FCC mixtures with 50% CAR after various milling
Figure 2: DSC thermograms of various CAR-FCC mixtures after 90 min of milling
In vitro drug release showed that samples containing 60 and 80% CAR did not significantly improve the release of CAR compared to either the neat amorphous or crystalline CAR. Samples containing 50% CAR did improve the drug release but showed extensive drug precipitation from the supersaturated solution as of about 60 min into the dissolution study. However, samples with 20-40% CAR showed about 3-fold increase is solubility compared to the neat forms of the drug at a dissolution time of 20 min and maintained supersaturation even after 360 min of dissolution testing (Fig.3).
In summary, co-milling FCC and CAR produced amorphous carvedilol. CAR-FCC samples containing 30% CAR and below were physically stable at dry storage conditions. The maximum drug load was found to be between 30-40% CAR. Improved drug release was observed for these systems.
Figure 3: In vitro drug release of crystalline and amorphous CAR and CAR-FCC samples
From this study, FCC improved the amorphization time, produced physically stable CAR-FCC formulations, improved dissolution and maintained supersaturation. This is indeed an all-round promising performance and leaves us with the question: should crystalline inorganic excipients be investigated more extensively to stabilize amorphous forms of drugs?
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#Oslo #Copenhagen #Amorphous #Formulation #physicalstability #Supersaturation
“Authors acknowledge funding from NordForsk for the Nordic University Hub project #85352 (Nordic POP, Patient Oriented Products).”
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Pharmaceutics (ISSN 1999-4923, click here) is an open access journal which provides an advanced forum for the science and technology of pharmaceutics and biopharmaceutics. It publishes reviews, regular research papers and communications. Covered topics include drug delivery and controlled release; pharmaceutical technology, manufacturing and devices; physical pharmacy and formulation; nanomedicine and nanotechnology; pharmacokinetics and pharmacodynamics; biopharmaceutics; drug targeting and design; gene and cell therapy; biologics and biosimilars; clinical pharmaceutics. Pharmaceutics is indexed by SCIE (IF 4.773, ranks 26/267 (Q1) in the category of Pharmacology & Pharmacy), PubMed and Scopus; it also is a member of DOAJ.
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Cryomilling as manufacturing technique to produce ASDs, a technique as gentle as generally assumed or rather not?Written by Timothy Pas
In this short communication, on current hot topics in the drug delivery and disposition lab, a chemical (and physical) evaluation of cryogenic milling to manufacture amorphous solid dispersions (ASDs) is provided to support novel mechanistic insights in the cryomilling process. Cryogenic milling devices are being considered as reactors in which both physical transitions (reduction in crystallite size, polymorphic transformations, accumulation of crystallite defects and partial or complete amorphization) and chemical reactions (chemical decomposition, …) can be mechanically triggered. Degradation of both APIs (Cinnarizine, Fenofibrate, Indomethacin and Naproxen) and polymers (HPMC, PVP, PVPVA, BSA and Gelatin 50PS) was observed and hence further characterized in depth by means of different analytical tools. Results demonstrated APIs to be more prone to chemical degradation in case of presence of polymer. A significant reduction of the polymer chain length was observed and in case of BSA denaturation/aggregation occurred. Hence, mechanochemical activation process(es) for amorphization and ASD-manufacturing cannot be regarded as a mild technique, as generally put forward, and one needs to be aware of potential chemical degradation of both API and polymer.
Spray drying is widely used in pharmaceutical manufacturing to produce microspheres from solutions or suspensions. The mechanical properties of the microspheres are reflected by the morphology formed in the drying process. In suspension drying, solids dissolved in the carrier liquid may form bridges between the suspended primary particles, producing a microsphere structure which is resistant against mechanical loads. Experiments with individual, acoustically levitated droplets were performed to simulate the drying of suspension droplets in a spray drying process.
One of the biggest problems in the manufacturing of high-quality low-dose inhalation products, is dose uniformity of filled capsules . Our approach towards a scientific qualification of dosator nozzles for low-fill weight (1–45 mg) capsule filling comprises a decoupling of the filling process in dynamic and static mode tests, whereas the latter was carried out using a novel filling system, i.e. stand-alone static test tool, developed by us.
Cold compaction of powder is important for many industrial processes, e.g., for the production of green bodies before sintering of metallic or ceramic parts in mechanical engineering, pellets for mineral or animal food industry or the production of tablets in the pharmaceutical industry. The final powder compact requires a minimum strength as otherwise it would disintegrate during processing, transportation or storage. Experiments can be used to adjust the process to get the desired compact strength. This is time-consuming, as process parameters change often, e.g., the geometry of the machine tools or the powder properties. Hence, reliable numerical models to predict the properties of compacts with simulations are crucial.
Controlled expansion of supercritical solutions: an alternative method for producing nanoparticles with supercritical carbon dioxideWritten by Jenni Pessi
Poly(lactic-co-glycolic acid) (PLGA)-based microparticles offer a great potential as parenteral controlled drug delivery systems . Different types of drug release patterns can be obtained from PLGA microparticles, in particular mono-, bi-, or tri-phasic drug release kinetics. Interestingly, yet the underlying mass transport mechanisms in PLGA microparticles are not fully understood, despite their great practical importance. This can be attributed to the complexity of the involved mass transport mechanisms. The aim of this study was to better understand the mass transport mechanisms controlling drug release from PLGA microparticles. Importantly, new insight was gained based on the experimental monitoring of the swelling kinetics of single microparticles.
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Ensuring thermodynamic stability of amorphous solid dispersions by predicting drug-polymer solubilityWritten by Matthias Manne Knopp, Rene Holm and Thomas Rades
The potential of amorphous solid dispersions to improve the solubility, dissolution rate and bioavailability of poorly water soluble drugs is well known. However, the number of formulations that have made it through to the market is limited because of the unstable nature of the amorphous form, which often results in recrystallization of the drug with the subsequent loss of the solubility and dissolution advantages. Thus, ensuring the stability constitutes a major challenge in the development of amorphous solid dispersions.
For the first time, an appropriate solid dosage form was developed for a co-amorphous drug-amino acid formulation, demonstrating the high physical stability for the particular system during further processing to tablets and during long-term storage thereof.
We have developed a new technique to better understand what happens to the microstructure inside a tablet during rapid disintegration.