 and the ability for solubilization (182,194,195). Hence, it cannot be excluded that changes in crystallinity and solubility due to polymorphic transition may have a significant impact on in vitro and in vivo drug release profiles (182). Along with an optimal dissolution rate, taste masking is often an important objective in formulation development (33,43,196,197). This is usually evaluated in sensory studies with trained volunteers (33,(198)(199)(200). Some studies also involve cats, which are sensitive to bitterness and scorn bitter food with insufficient taste masking (197). A simple in vitro method is the use of a disintegration tester (1 min stirring, pH 7,4) for the evaluation of the short time release amount in a pH close to that in the mouth (196), but also the results of a test of the first minutes of dissolution have been utilized (201). Another method reported is the mini column method, which represents a release test that attempts to simulate the anatomy and physiology of the oral cavity (201,202). A more sophisticated method is the measurement of dissolved samples with an electronic tongue, which consists of different potentiometric sensors and a pattern recognition system (203,204) (Table III).

Strategies for Controlling Polymorphism and Formulation Stability
Several approaches to control lipid polymorphism are conceivable, whereby only some have been applied in the existing literature: & Tempering during processing: Process temperatures are kept between the melting point of the instable αand stable β-form, in the area where the direct recrystallization of the stable β-form predominates over the β′-form (205). This prevents the formation of fractal structures (159) and the alteration of the dissolution profile due to morphological changes during storage. The recrystallization of the thermodynamically stable β-form is significantly slower than of the α-form. This may result in processing difficulties such as agglomeration in a fluid bed melt coating process or incomplete resolidification after spray chilling in a spray dryer. Melt extrusion is an appropriate technique to generate storage stable extrudates with this technique (142). & Tempering after processing (Bmaturing^): In the first step recrystallization of the instable α-form is enabled by ensuring optimum process conditions. Maturing is performed after the process at elevated temperatures below but close to the melting point of the instable α-form. The maturing step is time consuming and may require additional equipment (e.g., a drying chamber).
Alternatively, a fluid bed coater can be used for that step, as this prevents the formation of agglomerates. The α → β transformation causes the formation of fractal structures and the alteration of the dissolution profile before and after maturing (64,66,146). A complete transformation is essential for achieving a storage stable formulation. & Addition of crystallization seeds (Btemplate effect^) The stable β-form or material with a comparable saturation grade and a chain length difference of n≤4 can be used as seed material (177). The seed material is added to the molten lipid in the solid state. The presence of seeds acting as templates should accelerate the direct recrystallization of the molten material into the stable β-form (67,177). In case the stable β-form recrystallizes directly from the melt during the process, fractal structures should be avoided (159,164). When seed material is applied in form of a spraying suspension, the amount is limited to prevent nozzle clogging. The efficiency of this measure in accelerating the recrystallization and its effect on the purity of the stable phase haven't been analyzed in detail yet. & Avoidance of melting: The polymorphic transformation of most lipid excipients is monotropic. That means that if melting of the raw material, which is usually provided by the supplier in the stable β-form, can be avoided, the storage instabilities due to polymorphic changes can be eliminated. The challenge herein lies in the processability. Solid lipid excipients with a critical polymorphic behavior should either have a  (186) TD-NMR Solid fat content (SFC) Spreadability, firmness, mouth feel, processability and stability suitable viscosity or have to be combined with an excipient that has an appropriate viscosity and/or shows no polymorphism or transforms into the stable form during or immediately after resolidification (161,(207)(208)(209). In the case of aiming at a controlled release formulation, the formation of a physical mixture between drug and lipid excipient might be the wrong path as the dissolution rate of the physical mixtures may be higher than that of the solidified melt-dispersion (140,210). & Addition of polymorphic modifiers: Several emulsifiers are known to have a significant impact on the crystallization (e.g., nucleation rate, crystal growth and morphology) and polymorphic transition of lipid excipients (211,212). Although numerous publications exist on this topic, the majority of these studies discuss applying commercially available additives, which often consist of a chemical mixture with high heterogeneity and differ in their composition between different suppliers and even batches (211). Additional effects such as their concentration, kind of lipid, degree of undercooling as well as the use of agitation may have a significant influence on the crystallization and polymorphic process (211). Most of the application examples derive from and are addressed to the food industry and only a few studies are specific to the pharmaceutical industry (131,162,213,214). There are several examples how modifiers can impact the polymorphism: Sucrose esters obstruct the α → β and β′ → β transition in tristearin and hydrogenate sunflower oil due to their high rigidity and some representatives (e.g., P-170, S-170) also affect the crystal size of the high-melting fraction of milk fat (215)(216)(217). Garti et al. claimed that solid emulsifiers such as Span 40 (sorbitan monopalmitate), Span 60 (sorbitan monostearate), Span 65 (sorbitan tristearate) as well as glyceryl monostearate were able to stabilize the α-form and prevented the transformation into the stable β-form in tristearin (218,219). However, ageing Dissolution tester I/II, data fitting to mathematical kinetic models for controlled release (e.g., zero order) or immediate release (30,57,106,188) In vitro prediction of lipid digestion in vivo Dissolution with biorelevant medium; in vitro lipolysis with pancreatin, construction of IVIVC-model in case in vivo data is available (9,182,189,190,191) Storage stability at accelerated or intermediate conditions Evaluation of quality attributes (e.g., dissolution, taste) (43, 91,138,139) experiments at room temperature revealed that only a few molecules (e.g., triglycerol-l-stearate, sorbitan monostearate) with a suitable dimension of the hydrophilic moiety (Bbutton syndrome^) were able to preserve a certain amount of the α-form for a longer storage time (218). As the effect on polymorphism depends on the chemical and structural nature of the lipid and emulsifier, in principle it is conceivable that the stabilization of the αform during storage may be feasible to some extent. Nevertheless, this approach is associated with a high risk of transformation into the stable β-form in particular at higher storage temperatures. A more promising approach is the addition of emulsifiers to accelerate the transformation into the stable β-form. In particular, liquid or semisolid emulsifiers such as different polysorbates (Tween 60, 65, 80) and sorbitan monolaurate (Span 20) were proven to promote the α → β transformation due to an increase in molecular mobility (218,220). In the pharmaceutical industry this approach was used to coat N-acetylcysteine in a fluid bed coater with a coating consisting of tripalmitin and polysorbate 65 (162). As an advantage, the process temperatures can be kept to a minimum, which is preferable for drugs sensitive to heat, and the transformation and morphological changes will be complete before storage. However, it must be borne in mind that phenomena apart from polymorphism can lead to storage instabilities in particular if a liquid or semi-solid emulsifier is used in a greater amount (e.g., phase separation). Furthermore, the application of a higher amount of low-melting excipients can pose a problem if melt coating (e.g., fluid bed coating) or fast recrystallization in general is required. Thus, it is wise to take the time and effort for pre-formulation studies exploring the polymorphic and morphological behavior (e.g., crystal size, blooming, phase separation etc.) at different conditions (e.g., temperature, cooling and recrystallization rates, concentration etc.). & Selection of excipients without/with stable polymorphism Waxes such as carnauba wax, bees wax and stearyl stearate are stated to be non-polymorphic materials (40,46,221), which avoid storage instabilities associated with polymorphic changes. In particular the high melting point and brittleness of carnauba wax can induce processing problems such as nozzle clogging. Carnauba wax and bees wax have been most frequently used for controlled release formulations, but also immediate release is feasible with the addition of dissolution enhancers. Polyglycerides are said to be non-polymorphic, but stable in the αcrystalline form (222,223). The amount of glycerol-and esterified fatty acid molecules contributes to the HLB and can be adjusted in a wide polarity range and oligoglycerols with a degree of polymerization of up to 10 are approved by the FDA (224). Polyglycerol bears more functional groups for modification than PEG, and therefore shows a higher adaptability to different requirements such as the melting point or viscosity. However, these materials have been