Fused-deposition modelling or extrusion-based 3D printing is a flexible manufacturing technique and can be used for dose personalisation. At  the moment, the production of 3D printed dosage forms is still an empirical process which requires a huge time investment to screen and adapt different formulations according to the trial-and error principle, especially for researchers new to the field.(1) It is known that material properties of the filaments greatly impact the printability and determine the window of process conditions.(2) Therefore, the optimal rheological, thermal and mechanical properties of the feedstock-material should be characterized, in combination with their ideal process settings to achieve a successful end-product. The aim of the present study was to focus on the causality of a variety of printing failures, and linking these to key material properties and simple mathematical equations describing the 3D printing process. The study is intended to serve as a guide to speed up future filament development by identifying root causes of a printing failure and providing solutions to overcome these.

Despite the recent commercialization of several drug products manufactured through continuous manufacturing techniques, knowledge on the formulation aspect of these techniques, such as twin screw wet granulation, is still rather limited. Previous research from our group identified lactose/MCC/HPMC as a robust platform formulation for several model formulations, although granulation of the high-dosed, poorly soluble API mebendazole proved challenging (Portier et al., 2020). Therefore current research evaluated the effect of the binder addition method as well as surfactant addition when using PVP, instead of HPMC.

In this work, the insoluble hydrophobic polymer ethyl cellulose (EC) was investigated as a potential carrier for the formulation of amorphous solid dispersions (ASDs). Insoluble carriers have recently gained more and more attention due to their unique drug release mechanism which is based on a diffusion process [1,2]. As a result of this diffusion process, a more gradual build-up towards supersaturation is created compared to ASDs based on a water-soluble polymer and ideally, the ASDs based on an insoluble carrier are able to maintain supersaturation for a longer period of time.

Figure 1: Composition of the ternary ASDs based on EC as an insoluble carrier. Focus of this study was to assess the effect of the miscibility and the ratio of EC/PIA on the pharmaceutical performance of the ASDs. Indomethacin was used as a model drug.

The aim of this research was to investigate whether a surface coating technique could be developed that can predict the phase behavior of amorphous solid dispersions (ASDs) coated on beads. ASDs of miconazole (MIC) and poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA) in methanol (MeOH) were studied as a model system.

Physical instability arguably is the major challenge in using neat amorphous active pharmaceutical ingredients in everyday tablets and capsules [1]. 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 [2]. This temperature, however, can be very low, and thus makes stabilization of neat amorphous drugs practically difficult in most cases [2]. 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 [4]. 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 [8]. 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).


 [1] M. Rams-Baron, R. Jachowicz, E. Boldyreva, D. Zhou, W. Jamroz, M. Paluch, Physical Instability: A Key Problem of Amorphous Drugs, in: M. Rams-Baron, R. Jachowicz, E. Boldyreva, D. Zhou, W. Jamroz, M. Paluch (Eds.) Amorphous Drugs: Benefits and Challenges, Springer International Publishing, Cham, 2018, pp. 107-157.

[2] E.O. Kissi, H. Grohganz, K. Löbmann, M.T. Ruggiero, J.A. Zeitler, T. Rades, Glass-Transition Temperature of the beta-Relaxation as the Major Predictive Parameter for Recrystallization of Neat Amorphous Drugs, J. Phys. Chem. B, 122 (2018) 2803-2808.

[3] M.T. Ruggiero, M. Krynski, E.O. Kissi, J. Sibik, D. Markl, N.Y. Tan, D. Arslanov, W. van der Zande, B. Redlich, T.M. Korter, H. Grohganz, K. Löbmann, T. Rades, S.R. Elliott, J.A. Zeitler, The Significance of the Amorphous Potential Energy Landscape for Dictating Glassy Dynamics and Driving Solid-State Crystallisation, Physical Chemistry Chemical Physics, 19 (2017) 30039-30047.

[4] P.J. Marsac, S.L. Shamblin, L.S. Taylor, Theoretical and Practical Approaches for Prediction of Drug–Polymer Miscibility and Solubility, Pharmaceutical research, 23 (2006) 2417.

[5] S.J. Dengale, H. Grohganz, T. Rades, K. Löbmann, Recent advances in co-amorphous drug formulations, Advanced Drug Delivery Reviews, 100 (2016) 116-125.

[6] E.O. Kissi, G. Kasten, K. Löbmann, T. Rades, H. Grohganz, The Role of Glass Transition Temperatures in Coamorphous Drug-Amino Acid Formulations, Mol Pharm, 15 (2018) 4247-4256.

[7] K.K. Qian, R.H. Bogner, Application of mesoporous silicon dioxide and silicate in oral amorphous drug delivery systems, J Pharm Sci, 101 (2012) 444-463.

[8] E.O. Kissi, M.T. Ruggiero, N.-J. Hempel, Z. Song, H. Grohganz, T. Rades, K. Löbmann, Characterising glass transition temperatures and glass dynamics in mesoporous silica-based amorphous drugs, Physical Chemistry Chemical Physics, 21 (2019) 19686-19694.

Check out this commented presentation by Anne Linnet Skelbæk-Pedersen

Here's a commented presentation from Jerneij Stukelj from the University of Helsinki, Finland.

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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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.

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