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Radiation-induced in situ amorphization Featured

Written by Nele-Johanna Hempel and Korbinian Löbmann from the Department of Pharmacy, University of Copenhagen
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In situ amorphization is a recent approach in the preparation of amorphous solid dispersions (ASD). Compared to common preparation methods of ASDs, such as spray-drying and hot-melt extrusion, during in situ amorphization, the ASD is only obtained in the final dosage form, e.g. a tablet. In situ amorphization can take place as the final manufacturing step or at the site of the patient, i.e. directly before administration. As a physical mixture of the crystalline drug and polymer are used during manufacturing, issues such as the poor flowability of amorphous powders are circumvented. Furthermore, direct compaction is potentially possible and manufacturing steps regarding the preparation of the powder of the ASD are unnecessary. Physical instabilities of the ASD due to storage or drug loadings above the thermodynamic saturation solubility are not of concern if the in situ amorphization takes place directly before administration, as storage times can be kept short. Therefore, using in situ amorphization, manufacturing, storage and drug loading limitations of commonly prepared ASDs can be overcome.

Up to 90% of drug candidates in the drug development pipeline are expected to show poor aqueous solubility, resulting in limited absorbance, bioavailability and therapeutic effect of the drug [1]. One of the approaches to overcome poor aqueous solubility of a drug, is the solid-state transformation of a crystalline drug into its amorphous form [2,3]. The amorphous form is a disordered, thermodynamically unstable solid-state, which usually requires stabilization to be suitable for drug delivery [4]. One of the most common approaches to stabilize the amorphous form of a drug is to molecularly disperse the drug into an (amorphous) polymeric excipient, i.e. the formation of an amorphous solid dispersion (ASD) [1,5-9]. Besides an increase in the solid-state physical stability and the gain in solubility compared to the crystalline drug, the polymers used in an ASD can additionally inhibit the precipitation of the drug upon super-saturation during dissolution [5]. Despite the advantages of the use of ASDs for drug delivery and the intensive research, the number of marketed products consisting of ASDs are considerably low. Challenges, such as the manufacturing of ASDs, physical stability upon longer storage periods, increased humidity and low drug loadings (commonly 20­30 wt%), limit the use of ASDs [10,11].  

The concept of in situ amorphization

In situ amorphization describes the transformation of the crystalline drug into its amorphous form, commonly in the form of an ASD, in the final dosage form, e.g. a tablet [12]. In situ amorphization can take place as the final manufacturing step or directly before administration. Using in situ amorphization, challenges regarding the manufacturing of the ASD can be circumvented. Furthermore, low drug loadings and physical stability are not of concern if in situ amorphization takes place directly before administration, as storage times can be kept short, making drug loadings above the thermodynamic saturation solubility become available.

Radiation-induced in situ amorphization

Microwave and laser radiation have been employed as radiation sources for in situ amorphization. Radiation-induced in situ amorphization has been described to follow a dissolution process of the drug into the polymer at temperatures above the glass transition temperature (Tg) of the polymer [13] (Figure 1).


Figure 1: Illustration of a) in situ amorphization inside a tablet using electromagnetic radiation; b) the dissolution process of the drug into the mobile polymer with increasing temperature and upon cooling (from left to right). The blue circles indicate the drug molecules, the red strings indicate the polymer.

As increased temperatures are necessary, heat must be generated inside the tablet upon exposure to radiation. Therefore, absorbing excipients are incorporated into the tablet formulation that absorb the radiation and generate heat. Additionally, as radiation-induced amorphization follows a dissolution process, the Noyes-Whitney equation (Equation 1) applies (and Stoke-Einstein equation for the diffusion coefficient; Equation 2), describing the dissolution rate of a solute (here: drug) into a solvent (here: polymer) [14,15]:

         dm/dt = A·D/h·(Cs - Cb) (Equation 1)

         D = k/(6πr)·(T/η)  (Equation 2)

where dm/dt = solute dissolution rate, m = mass of dissolved material, t = time, A = surface area of the solute particle, i.e., the crystalline drug particles, h = thickness of the diffusion layer, Cs = particle surface (saturation) concentration; i.e. drug-polymer solubility, Cb = concentration in the bulk solvent/solution; i.e., drug concentration in polymer, D = Diffusion coefficient of the solute in solution, i.e. the polymer, k = Boltzmann constant, T = absolute temperature, η = viscosity of the solvent, i.e. the polymer, r = radius of the solute molecule.


Microwave-induced in situ amorphization
Microwaves are electromagnetic waves, which commonly have a fixed frequency of 2.45 GHz in a household microwave oven. Absorbing excipients usually contain dipoles, which align to the alternating electromagnetic field and generate heat upon exposure. For microwave-induced in situ amorphization, until now, three different absorbing excipient have been identified: water [13,16-18], glycerol [19] and polyethylene glycol (PEG) [20]. Water was used in form of sorbed water [13,16,18] and crystalline hydrates [17] inside the tablet formulation. Sorbed water additionally acted as a plasticizer lowering the Tg of the polymer to temperatures reachable during exposure to microwave radiation [16,18]. The absorbing excipient glycerol furthermore allowed the formation of a super-saturated ASD upon cooling [19]. Also, tablets containing the drug celecoxib (CCX), PEG as an absorbing excipient and the polymer polyvinylpyrrolidone (PVP) resulted in the formation of a supersaturated ASD upon cooling with a drug load of 50 wt% [20].

In line with Equation 1, the use of small drug and polymer particles inside a tablet, increased the dissolution rate and a fully amorphous ASD upon exposure of the tablet to 10 min of microwave radiation was reported [13]. Furthermore, it could be shown with tablets containing CCX and PEG, that the dissolution rate increased with an increasing diffusion coefficient, i.e. with increasing temperature or decreasing viscosity resulting in faster complete amorphization upon exposure to microwave radiation, which is in line with Equation 2 [21].

Laser-induced in situ amorphization
Similar to the use of microwave radiation, laser radiation is an electromagnetic wave and therefore an absorbing excipient is necessary inside the formulation to allow for heat generation upon exposure to laser radiation. As an absorbing excipient for laser-induced in situ amorphization, plasmonic nanoparticles (PNs) were identified. PNs show unique photo-thermal properties due to surface plasmon resonance [22,23] and can absorb light in the near-infrared spectrum [24-26].

Using low amounts (≤ 0.25 wt%) of PNs inside tablets consisting of up to 50 wt% CCX and PVP, complete amorphization could be achieved by exposure to laser radiation in as fast as 180 sec [26]. Similar to findings reported for microwave-induced in situ amorphization [27], the use of a low Mw grade of PVP was advantageous for laser-induced in situ amorphization compared to a higher Mw of PVP, due to a lower viscosity [28]. Additionally, in line with Equation 2, using tablets with PVP and three different model drugs, the use of the drug with a small molecular size resulted in an increase in the dissolution rate [28].

Recently, the approach of laser-induced in situ amorphization of CCX was also shown for four other polymers besides PVP. It was found that the different physicochemical properties of the polymer as well as the solubility of the drug in the polymer, resulted in different heating rates upon exposure to laser radiation [29].

The recent investigations of radiation-induced in situ amorphization, have led to the understanding that the formation of an ASD inside the tablet follows a dissolution process into the mobile polymer at elevated temperatures as described by the Noyes-Whitney equation. Several absorbing excipients have been identified to obtain complete amorphization upon exposure to microwave or laser radiation.

The interested reader is further referred to a recent comprehensive review about microwave-induced in situ amorphization [30].


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