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?
Read the full version of the article here
#Oslo #Copenhagen #Amorphous #Formulation #physicalstability #Supersaturation
“Authors acknowledge funding from NordForsk for the Nordic University Hub project #85352 (Nordic POP, Patient Oriented Products).”
 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.
 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.
 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.
 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.
 S.J. Dengale, H. Grohganz, T. Rades, K. Löbmann, Recent advances in co-amorphous drug formulations, Advanced Drug Delivery Reviews, 100 (2016) 116-125.
 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.
 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.
 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.