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ASDs should have good physical and chemical stability and provide enhanced API dissolution and oral bioavailability. Optimal performance can be delivered by single-phase amorphous mixtures of the API and a polymer, i.e., glass solutions with molecularly dispersed drug molecules in the polymer (Janssens and Van den Mooter 2009; Padden et al.2011). Molecular interactions play a key role in such systems.

They (1) ensure the long-term physical stability of the amorphous drug and (2) prevent drug precipitation from the supersaturated solution formed upon in vivo dis-solution. Miniaturized screening methods probe both of these aspects. The relevant drug–polymer interactions are briefly discussed below.

5.2.2.1 Drug–Polymer Interactions in the Solid State

The ability of polymers to inhibit crystallization in glass solutions is primarily related to the overall increase in the glass transition temperature (Tg) of the dispersion,

170 Q. Hu et. al which reduces the molecular mobility of the API at the normally encountered storage temperatures and relative humidity (Shamblin et al.1998; Bhugra and Pikal2008).

If a drug and a polymer are miscible to form a one-phase system, the glass transition temperature of ASD will lie in between the API Tgand the polymer Tg, depending on the composition of the system. If immiscible, however, the system will produce two separate glass transition temperatures of the drug and the polymer. The strong interactions between a drug and a polymer via hydrogen bonding, acid–base ionic interactions, dipole–dipole interactions, and hydrophobic interactions will favor the one-phase ASD system (Taylor and Zografi1997; Matsumoto and Zografi1999;

Khougaz and Clas2000; Miyazaki et al. 2004; Weuts et al. 2005; Marsac et al.

2006b; Rumondor et al.2009a; Yoo et al.2009).

Mode of ASD stabilization by polymers can also be attributed to interfering with the nucleation and crystal growth processes. It has been well documented that specific hydrogen bonding between drug and polymer inhibits nucleation process (Hancock et al.1995; Taylor and Zografi1997; Matsumoto and Zografi1999). In fact, other types of molecular interactions between a drug and a polymer can also interfere nucleation process of API (Van den Mooter et al.2001; Weuts et al.2005).

Moisture can disrupt drug and polymer interactions, promoting demixing of drug and polymer with eventual crystallization of the drug (Konno and Taylor2006; Ru-mondor et al. 2009b). Recently published work showed that the physical stability of solid dispersions depends on the hygroscopicity of the ASD and the strength of drug–polymer interactions (Rumondor et al.2009b; Rumondor et al.2009c, Rumon-dor and Taylor2010). Hygroscopic polymer tends to pose stability challenges and should be well protected from moisture.

Recently, Van Eerdenbrugh and Taylor (Van Eerdenbrugh and Taylor2011) ap-plied crystal engineering principles to arrive at an ab initio rank order of polymers for the ability of crystallization inhibition. The working hypothesis of this study was that polymers inhibit the crystallization of a drug better if the hydrogen-bonding interactions between the drug and the polymer are more favorable than those present in the crystalline drug. Relative strength of hydrogen bonding of drugs and polymers was calculated to assess the ability of a given drug–polymer mixture to prevent crys-tallization. The predicted rank order was in good agreement with the observation from an extensive experimental dataset. The crystallization inhibition was strongly dependent on the functional groups of the drug and polymer. As summarized in Table5.3, the results of this study facilitate the rational selection of polymers for the development of stable ASDs and even guide the design of novel polymers.

From a practical point of view, various analytical methods are commonly applied to study the solid phase behavior of ASDs (Table5.4). Their use in combination is generally recommended as each has its own advantages and limitations. FTIR, Raman, and solid-state nuclear magnetic resonance (SS-NMR) spectroscopy are generally used to investigate molecular drug–polymer interactions. Changes in the FTIR and/or Raman spectra (new bands, disappearing bands, widening and inten-sity changes of existing bands, or band shifts) can indicate such interactions. With SS-NMR changes of chemical shifts, relaxation times and/or cross-signals in HET-COR spectra (Pham et al.2010) may be induced by closer spatial proximity of the

5 Miniaturized Screening Tools for Polymer and Process Evaluation 171 Table 5.3 Predicted and observed best API–polymer combinations with favorable drug–polymer hydrogen bond interactions for optimal crystallization inhibition. (Adapted from data by Van Eerdenbrugh and Talyor2011)

Molecular API self-association will be most disrupted by polymers bearing strong acceptor groups that can effec-tively compete with the drug acceptor groups. Indeed, the best results were obtained with polymers bearing strong acceptors and no donors

Acidic NH groups E100 PVP PVPVA

As for the carboxylic acids, the best crystallization inhibiting performance was obtained for polymers con-taining strong acceptor groups that provide a competitive hydrogen bond alternative for the acidic N–H group

Alcohols E100

PVP PVPVA

As the OH group acts as a strong donor and medium acceptor, polymers with strong acceptors would be ex-pected to compete successfully for these donors. Indeed, the polymers having strong acceptors showed the best results in terms of crystallization inhibition

Amides and bases PSSA^d PAA^e PVP PVPVA

Competitive hydrogen bond formation would be ex-pected in the presence of polymers with strong donor and/or extremely strong acceptor groups. Accordingly, the polymers containing strong donors (PSSA and PAA) were the best crystallization inhibitors for this category of APIs, and polymers containing the very strong pyrroli-done acceptor group (PVP/PVPVA) also performed well. The lower performance observed for HPMC^fand HPMCAS^g is explained by the lower strength of its donors (compared to PAA/PSSA) and acceptors (com-pared to PVP/PVPVA)

aEudragit^®E100

bPoly(vinylpyrrolidone) (PVP, K 12, Ph. Eur., USP)

cPoly(vinylpyrrolidone-vinyl acetate) (PVPVA, K 28, Ph. Eur.)

dPoly(styrene sulfonic acid)

ePoly(acrylic acid) (Mv450.000)

fHypromellose USP, substitution type 2910, viscosity 6 mPa s

gHydroxypropylmethylcellulose acetate succinate, grade AS-MF

components in the drug–polymer system. However, SS-NMR cannot reliably distin-guish between force-like interactions and spatial proximity. Detailed characterization principle and application should be referred to Chap. 14.

5.2.2.2 Drug–polymer Interactions in Aqueous Media for ASD Feasibility An amorphous formulation gives rise to the higher apparent solubility than crystalline drug and become supersaturated (Brouwers et al.2009). The supersaturated solution

172 Q. Hu et. al Table 5.4 Commonly used analytical instruments to study ASD

Detection of: AFM^a DSC^b XRPD^c PLM^d FTIR^e Raman^f

gSolid state nuclear magnetic resonance spectroscopy

hPhase separation detectable at a nanometer scale (Newman et al.2008; Lauer et al.2011)

iAmorphous mixtures and strong drug–polymer interactions require the components in the system to be in close spatial proximity, which can be detected by SS-NMR

has the tendency to return to equilibrium by drug precipitation. Supersaturated con-dition can be maintained by incorporating the right polymers to the ASD. Polymer can modulate the dissolution rates and extents of precipitation by various modes as described below, and these effects should be considered in the selection of polymers for ASD. The most important factors that generally influence drug precipitation and, more specifically, the interaction between polymers and drug molecules are:

1. Polymer as a antinucleation agent: A polymer can inhibit nucleation and crys-tal growth of a drug by specific interaction with functional groups of the drug (Curatolo et al. 2009; Alonzo et al.2010). Polymers such as PVP, HPMC and HPMC-AS have been extensively studied for the amorphous stabilization effect in aqueous solution (Lindfors et al.2008; Miller et al.2008; Alonzo et al.2010).

2. Ionic interactions: Polymers with opposite charge to the drug can form ion pair complexes and stabilize drug solution (Warren et al.2013).

3. Hydrogen bonding: Increasing the number of hydrogen bonding sites increase the interaction with drug. Itraconazole interacts with HPMC stronger than with PVP (Miller et al.2008).

4. Viscosity of solution: High viscosity decreases the rate of molecular diffusion and molecular collision, retarding nucleation and crystal growth (Wyttenbach et al.

2013).

5. Molecular weight of polymer: High MW polymers interact with drug molecules strongly. This effect has been observed for large MW PVP and HPMC, which have been shown to maintain the supersaturation of itraconazole longer for a long period of time (Miller et al.2008). It can be attributed to either an increase in viscosity or large number of functional groups in the polymer chain that can interact with API.

5 Miniaturized Screening Tools for Polymer and Process Evaluation 173 6. Temperature: Interaction between drug and polymer is weaker at higher tem-peratures because of thermal motions of the molecules. The concentration of felodipine during dissolution of amorphous felodipine was higher at 25^◦C than at 37^◦C, suggesting that weaker drug–polymer interaction at higher temperature can be the cause of faster crystallization (Alonzo et al.2010; Wyttenbach et al.

2011).

7. pH shifts: The dissolution of ionic polymers or drugs will shift the pH of disso-lution media, which can influence the solubility and precipitation behaviors of drugs and polymers (Wyttenbach et al.2013).

8. Interfacial tension: Polymers can reduce the interfacial tension and prevent the aggregation of fine drug particles upon dissolution of ASDs. On the other hand, a decreased interfacial tension also can increase the nucleation and induce drug crystallization (Lindfors et al.2008).

9. Co-solvent effect of dissolved polymers: Polymers in solution can act as solubiliz-ers and increase the solubility of drugs, thus reducing the degree of supsolubiliz-ersaturation and the risk of drug precipitation (Rodríguez-Hornedo and Murphy1999; Warren et al.2010).

In addition, amorphous formulations often contain surfactants such as Tween 80, Span 80, TPGS, or Cremophor for a variety of reasons as processing aids. One should be mindful as the inclusion of surfactants to the ASD formulation can either prevent crystallization (Pouton 2006) or promote crystallization (Rodríguez-Hornedo and Murphy2004). Bile salt micelles and other lipids (e.g., digestion products) presented in the GI tract may help to maintain high levels of supersaturation of drugs.

In silico prediction of the in vivo dissolution behavior of amorphous systems is currently almost impossible. Thus, in vitro screening for the identification of suitable drug-excipient combinations with appropriate dissolution and/or high su-persaturation potential has become a vital step in the development of ASDs. Today, supersaturation screening is commonly carried out by solvent-shift approaches (e.g., the co-solvent quench method) or by dissolution testing (e.g., amorphous film dissolution in solvent-casting approaches). These topics are discussed further in Sect. 5.3.