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Monday, 25 February 2013 18:19

Co-Amorphous Drug Delivery Systems

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Formulation of co-amorphous drug systems

Using the amorphous form of a drug, instead of its crystalline counterpart is one way to enhance the bioavailability of poorly water-soluble drugs. However, in order to fully benefit from the solubility advantages of amorphous drugs, one needs to overcome phyisco-chemical limitations including poor physical stability associated with the amorphous form. Co-amorphous drug formulations are a novel and one of the most promising formulation approaches in this context, where the drug in its amorphous form is stabilized through strong intermolecular interactions with its co-amorphous low molecular weight partner molecule.

Background and Formulation Strategy

The formulation of a poorly water-soluble crystalline drug into its high energy amorphous form has been shown to be a promising approach to increase dissolution properties and thus bioavailability. However, due to their high internal energy, pure amorphous drugs often show fast recrystallization kinetics to the low energy (low solubility) crystalline state. Thus, the applicability of amorphous drugs is usually limited by their poor physical stability [1].

A high glass transition temperature (Tg) is often connected with improved physical stability of amorphous compounds. Below the Tg molecular movement is drastically reduced which lowers the chance of molecular reorientation and therefore, crystal nuclei formation and crystal growth [2]. Increasing the Tg by incorporation of the drug into polymers was the main idea behind solid dispersions or glass solutions. This is a sensible and promising approach, but so far has only lead to very few marketed products, which can be attributed to problems associated with solid dispersions such as limited solubility of the drug in the polymer or hygroscopicty of the polymers [3].

The idea behind the co-amorphous formulation approach is to stabilize the amorphous form of a drug by strong and specific molecular interactions between the drug and a low molecular weight partner molecule. These interactions, rather than merely a high Tg, will prevent the drug from recrystallization and thus ensure physical stability. For the drug to recrystallize, first the interactions need to be broken, second the molecules need to reorientate in the co-amorphous mixture and third like molecules need to meet and form a crystal nuclei. 

Drug-Drug combinations

Co-amorphous drug-drug formulations were introduced by Chieng et al. (2009) as new delivery systems for poorly water-soluble drugs that are suitable for combination therapy, i.e. with similar doses and pharmacological profile. The feasibility of this approach has been shown for several drug-drug combinations [5]. These initial studies concentrated on the basic solid-state characterization, molecular interactions, recrystallization and dissolution improvement.

The main research outcome was to establish the importance of molecular interactions in the physical stability of amorphous formulations. It could be shown that recrystallization is mainly driven by the absence of intermolecular interactions rather than a high Tg. These interactions are crucial for the physical stability of co-amorphous systems [4, 6, 7]. For example, specific interactions between the drugs indomethacin and naproxen resulted in the formation of a drug heterodimer in the co-amorphous blend [8]. For the drugs to recrystallize this heterodimer needed to disassociate and the molecules needed to reorientate themselves towards homodimers, which are then able to create a crystal nuclei (Figure 1).

The dissolution of the co-amorphous formulations was increased not only over the pure crystalline drugs but also over the pure amorphous drugs. The interacting nature in co-amorphous drug-drug mixtures furthermore resulted in a synchronized release, i.e. both drug molecules are dissolved in a pair wise fashion at a similar rate [6, 7]. It was also possible to show that plain molecular level mixing itself has a positive effect on the physical stability of co-amorphous formulations [9].

Drug-amino acid formulations

The co-amorphous formulation approach was further developed by Löbmann et al. (2013), introducing amino acids as low molecular excipients for these systems (Figure 3) [10, 11]. The need for suitable low molecular weight excipients was pressing, firstly to enable the formulation of co-amorphous single drug delivery systems and secondly to be able to compete with other amorphous formulation approaches, i.e. solid dispersions.

It was possible to produce highly stable co-amorphous drug-amino acid combinations with enhanced dissolution kinetics. The formulations showed strong intermolecular interactions between the drugs and the amino acids, and had markedly higher Tgs than the pure drug. Due to the low molecular weight of the amino acids, the total amount of “excipients” in these formulations was also rather low. Furthermore, amino acids can be regarded as generally safe because they are part of the daily nutrition. The co-amorphous drug-amino acid formulation approach may be regarded as an attractive alternative to the use of polymer based solid dispersions.

Outlook

We have demonstrated the huge potential of the co-amorphous formulation approachThis a completely new strategy in stabilizing the amorphous form of a drug and gives interesting and alternative opportunities for formulating poorly water soluble drugs into amorphous dosage forms. We are confident to further establish this formulation strategy for poorly water soluble drugs into a competitive platform technology.

References

[1] J. Aaltonen, T. Rades, Towards Physico-Relevant Dissolution Testing: The Importance of Solid-State Analysis in Dissolution, Dissolution Technologies 16 (2009) 47-54.
[2] B. Hancock, S. Shamblin, G. Zografi, Molecular Mobility of Amorphous Pharmaceutical Solids Below Their Glass Transition Temperatures, Pharmaceutical Research, 12 (1995) 799-806.
[3] T. Vasconcelos, B. Sarmento, P. Costa, Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs, Drug Discovery Today, 12 (2007) 1068-1075.
[4] N. Chieng, J. Aaltonen, D. Saville, T. Rades, Physical characterization and stability of amorphous indomethacin and ranitidine hydrochloride binary systems prepared by mechanical activation, European Journal of Pharmaceutics and Biopharmaceutics, 71 (2009) 47-54.
[5] R. Laitinen, K. Löbmann, C.J. Strachan, H. Grohganz, T. Rades, Emerging trends in the stabilization of amorphous drugs, International Journal of Pharmaceutics, DOI: 10.1016/j.ijpharm.2012.04.066 (2012).
[6] M. Allesø, N. Chieng, S. Rehder, J. Rantanen, T. Rades, J. Aaltonen, Enhanced dissolution rate and synchronized release of drugs in binary systems through formulation: Amorphous naproxen-cimetidine mixtures prepared by mechanical activation, Journal of Controlled Release, 136 (2009) 45-53.
[7] K. Löbmann, R. Laitinen, H. Grohganz, K.C. Gordon, C. Strachan, T. Rades, Coamorphous Drug Systems: Enhanced Physical Stability and Dissolution Rate of Indomethacin and Naproxen, Molecular Pharmaceutics, 8 (2011) 1919-1928.
[8] K. Löbmann, R. Laitinen, H. Grohganz, C. Strachan, T. Rades, K.C. Gordon, A theoretical and spectroscopic study of co-amorphous naproxen and indomethacin, International Journal of Pharmaceutics, DOI: 10.1016/j.ijpharm.2012.05.016 (2012).
[9] K. Löbmann, C. Strachan, H. Grohganz, T. Rades, O. Korhonen, R. Laitinen, Co-amorphous simvastatin and glipizide combinations show improved physical stability without evidence of intermolecular interactions, European Journal of Pharmaceutics and Biopharmaceutics, 81 (2012) 159-169.
[10] K. Löbmann, H. Grohganz, R. Laitinen, C.J. Strachan, T. Rades, Amino acids as co-amorphous stabilisers for poorly water soluble drugs - Part 1: Preparation, stability and dissolution enhancement, European Journal of Pharmaceutics and Biopharmaceutics, under revision (2013).
[11] K. Löbmann, R. Laitinen, C.J. Strachan, T. Rades, H. Grohganz, Amino acids as co-amorphous stabilisers for poorly water soluble drugs - Part 2: Molecular Interactions, European Journal of Pharmaceutics and Biopharmaceutics, under revision (2013).

PSSRC Facilities

The group of Prof. Thomas Rades in Copenhagen has extensive experience in formulation, drug delivery and physical characterization of solid drugs and dosage forms. In particular, research has focused on in depth characterization of amorphous forms of drugs, new analytical techniques for the investigation of solids, and the development of new concepts for the stabilization of amorphous systems.

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