Amorphization of Drugs for Transdermal Delivery -a Recent Update

Dispersing amorphous drugs in miscible hydrophilic polymers like hydroxypropyl methyl cellulose, polyvinyl pyrrolidone (PVP), grafted copolymer like Soluplus^® etc., is the most common approaches to inhibit recrystallization. It is like solid dispersion, where amorphous drug is dispersed within a polymeric carrier when the carrier can be fully or partially amorphous. For transdermal delivery, the solid dispersion of the drug should exist as an amorphous solid dispersion containing hydrophilic polymers. These polymers act in two ways; by forming intermolecular hydrogen bonding with the drugs and filling the voids in the supersaturated solutions restricting molecular mobility. Both mechanisms help retarding the nucleation rate and recrystallization. Polymers not only help to stabilize the system but also help drug permeation from transdermal delivery. They help in a massive increase of saturation by the drug increasing thermodynamic activity. Use of other additives like acrylate polymer, Eudragit different grades like EPO, RLPO or RSPO is also used as crystallization inhibitors in the amorphous transdermal systems. Eudragit^® EPO and RLPO were shown to reduce the crystallization of estradiol in a transdermal patch at 1:20 drug: Eudragit^®.

Sometimes, apart from the solubilization effect of the polymer, enhancement of solution activity causes a remarkable increase in transdermal flux. The cumulative amount of artemisin permeation through rabbit skin throughout 8 hrs was observed 5–10 times higher in the case of PVP K30 containing solid dispersion. The flux enhancement ratio of solid dispersions, calculated concerning supersaturated pure drug solution, increased 5–11 folds. The study also reported an increase in flux with increasing polymeric concentration. A similar type of observation is noted on hydrophilic polymeric excipients. Other aspects of the permeation enhancing effect of PVP K30 are noted. PVP tends perturbation into the hydrophobic region of the skin lipid bilayer and improves the fluidity of the region and local drug concentration. In the case of Eudragit^®, permeation enhancement has also been noted. Eudragit^® EPO increased estradiol permeation in ex-vivo permeation study through guineapig skin for all permeability parameters like steady-state flux, diffusivity, permeability coefficient. With increasing Eudragit^® concentration, drug permeation was also enhanced. An increase in the rate of hydration is one cause of permeation enhancement apart from maintaining the amorphous or metastable drug state.

A critical issue of polymer-based amorphous drug dispersion is the adequate quantity of polymers or excipients required to prevent drug crystallization. Often it becomes high, restricting the drug loading and hence the commercial feasibility of the formulation. Coamorphous system can overcome this problem. One drug is mixed with another drug or low molecular weight compound in this system, which stabilizes each other, restricts crystallization, and maintains a single-phase homogenous amorphous system. The requirement of excipient usually remains lower than the amorphous solid dispersion due to the presence of a low molecular weight compound used as coformer.

Recently few coamorphous systems have been reported where the poor soluble API is mixed with another coformer and dispersed in a viscous vehicle, often PEG 400 . Intermolecular interaction like hydrogen bonding and ionic interaction between the two drugs or drug and coformer is the primary factor of forming a stable amorphous system. Such interactions can be evidenced by FTiR and NMR studies. In FTiR, the absence or shift in the hydrogen bond-forming group in coamorphous mixture may indicate intermolecular interaction. Acyclovir coamorphous formulation was prepared where citric acid was used as the coformer. O–H peak at 3495 cm⁻¹ vanished in the citric acid IR spectra while N–H stretching peak frequency was shifted to a higher side. Another O-H stretching peak was not observed in coamoprhous mixture. Such absence or shift in IR peaks is evidence of H bonding between acyclovir and citric acid. NMR analysis can be used to study the interaction between drug and conformer, where a downshift of proton (1H1) signal can be observed due to a change in electron density by intermolecular interaction. Recrystallization during storage of coamorphous materials can be easily identified by powder X-ray diffraction study (PXRD), where the absence of drug crystal peaks at characteristic 2-theta angle establishes the drug amorphousness. Thermal analysis and detection of glass transition (T_g) of the amorphous sample also indicate the recrystallization nature and storage stability. It is considered that physical instability or recrystallization would be negligible if storage temperature lies 50° below the glass transition.

For skin permeation enhancement, either enhanced thermodynamic activity due to supersaturation and/or the presence of coformer (often acts as permeation enhancer) are considered significant. In some cases, coformer used in the system also acts as a permeation enhancer. Atenolol supersaturated coamrophous system was developed where urea was used as coformer . Skin permeation through mice skin was observed the highest from the supersaturated coamoprhous system (Figure 2). Permeation flux of atenolol was noted 2.9 and 6 folds higher in coamorphous system than pure atenolol saturated suspension and atenolol- urea saturated suspension, respectively. Urea has played a dual role of crystallization inhibitor and penetration enhancer in this study. In another recently published study, piroxicam coamoprhous system was developed. The cumulative amount of piroxicum permeated and steady-state flux through mice skin was almost doubled in coamorphous dispersion of piroxicum and citric acid (coformer) compared to a pure drug suspension and physical mixture of drug-coformer. However, in this work, the degree of supersaturation was primarily responsible for enhanced skin permeation rather than the skin penetration-enhancing property of citric acid.