Post-extrusion stability

Post extrusion stability can be further divided into two categories. Firstly, short term stability which is usually correlated with the immediate solid state change upon extrusion and the impact of downstream processes. Secondly is the long term stability which is the main hurdle for product commercialization.

1.5.1.1.1. Short term stability

Mechanical stress such as milling can induce recrystallization of API after extrusion process.

Recrystallization of itraconazole (ITZ) was found to be 25% and 14% in the milled and unmilled Eudragit E100 extrudate, respectively at low loading of ITZ (Six et al., 2002). At high loadings of ITZ, the percentage of recrystallization increased dramatically in the milled extrudates as compared to the unmilled extrudates of Eudragit E100 which showed 60% and 20% of ITZ crystalline content, respectively (Six et al., 2002). This is due to the alteration in the kinetics of recrystallization of ITZ by the polymer molecules in the unmilled samples that hinder the conversion of the amorphous API to its more stable crystalline form. Similarly, milling of HME R103757 (water soluble microsomal triglyceride transfer protein inhibitor) – HPMC extrudates causes extensive recrystallization of the R103757 which was originally amorphous after extrusion (Verreck et al., 2004).

Albers et al. (2009) demonstrated that external phase inclusion of polymer (40 mg HPMC) into the milled HME extrudate could delay recrystallization process of the system (Albers et al., 2009).

Even though the downstream process of milling might affect the physical stability during the production of extrudate; there are other studies indicated that milling of HME extrudate has no effect on its physical stability (Albers et al., 2009, Forster et al., 2001b).

1.5.1.1.2. Long term stability

As discussed in Chapter 1.5.1, HME products has frequently presented its good physical stability due to the intense mixing, high compression and solubilisation of molten material in HME process (Young et al., 2005). In the subsequent sections, factors dictating the physical stability of HME extrudate will be further discussed.

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Steric hindrance / polymer ratio

Addition of polymer to the API has been shown to enhance physicochemical stability of an amorphous API by reducing the interaction among API molecules via steric hindrance and increasing the energy barrier for nucleation (Yang et al., 2010a, Six et al., 2004). Higher molecular weight (MW) of polymer has reported to exert bigger impact by hinder the rearrangement of drug molecule and thus reduce rate of crystallization (Prodduturi et al., 2005). Besides, the ratio of the polymer content is also playing a role in recrystallization inhibition. For instance, Yang et al.

(2010a) reported the decrease in recrystallization rate of efavirenz when the ratio of polymer was increased. This is due to the greater number of efavirenz molecules that entrapped in a higher percentage of PVP polymer matrix (Yang et al., 2010a).

In a study, hydrophilic polymers are used as crystallization inhibitor e.g. PVP K-25, Polycarbonil, PEG3350, Poloxamer 188 and Polyethylene oxide (Bruce et al., 2007). The use of these hydrophilic polymers in the composition of extrudate has shown to reduce the recrystallization rate of the API in comparison to the similar formulations without the inhibitors. This is because of the increase of API solubility in the matrix containing both polymer and hydrophilic carrier and which reduces the tendency of recrystallization (Bruce et al., 2007).

Drug-polymer interaction

Interaction between the polymer carrier and drug substance could also impart positive stability to an extrudate. A study conducted by Foster et al. (2001b) suggested the presence of hydrogen bonding between the API and polymer in the investigated extrudate. In that study, the authors proposed that the quantity of these hydrogen bonds is inversely correlated to the ability of water penetration upon storage. With a lower degree of hydrogen bonds between the API and polymer, the proton acceptor sites of the polymer will be exposed and enable its interaction with any absorbed water molecules (Forster et al., 2001b). This causes plasticization of polymer and subsequently promotes recrystallization of API. Hence, the choice of carrier can critically in determine the physical stability of a HME product.

Water content of products

Water content can profoundly affect the physical stability of a product (Forster et al., 2001b). It is particularly important for hygroscopic drugs. For instances, Foster et al. (2001) performed a physical stability tests on HME SD of indomethacin, lacidipine, nifedipine and tolbutamide. The study showed that nifedipine recrystallizes more than indomethacin attributed to the higher water

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content of the former drug as compared to the latter (Forster et al., 2001b). Besides, the high water uptake of Δ⁹ -tetrahydrocannabinol- hemiglutarate extrudate has caused a high percentage of drug degradation when the product is expose to humid condition (Thumma et al., 2008a). Similarly, high moisture content of HME ketoconazole films has resulted in high degradation of ketoconazole after 6 months storage in humid condition despite the good stability of the product post extrusion (Mididoddi and Repka, 2007).

Another study carried out by Six et al. (2003) has shown that the water content can cause phase separation and a significant change in Tg of a binary HME system of ITZ-HPMC. The authors suggested that the presence of water in the HME system could impart 2 major effects. Firstly, water acts as a plasticizer to the amorphous system. Secondly, water could interrupt the formation of hydrogen bonds between drug and polymer (Six et al., 2003a).

The water content of a product is highly dependent on the storage humidity. Greater recrystallization of HME guaifenesin (GFN) in Eudragit® L10055 or Acryl-EZE® was seen in higher humidity storage condition (Bruce et al., 2010). In that study, the effect of RH cycling was also tested. The HME GFN guaifenesin Eudragit® L10055 were exposed to two different cycles.

The first batch of the sample was stored firstly in a low RH condition (17%) for 6 days, then transferred to a high RH condition (78%) for 12 days and subsequently returned to the low RH condition. The second batch of sample was started with storing in high RH condition (78% ) for 6 days followed by low RH condition in the intermediate stage and finally returned to the high RH storage condition. The results indicated that crystallization occurred rapidly when the samples was introduced to the high RH condition, and these crystals remain permanently in the samples to further induce the recrystallization process even though low RH storage conditions were used (Bruce et al., 2010).

Addition of excipient

Addition of excipient such as surfactant, disintegrant or lubricant has shown to benefit the dissolution performance of solid dispersion formulation (Ghebremeskel et al., 2006, Ghebremeskel et al., 2007). However, these excipients could potentially alter the physical stability of the drug product. A study reported that higher percentage of triacetin (TA) in polyvinyl acetate phthalate (PVAP) capsules has led to a higher moisture uptake of the product upon storage as compared to the similar product with a different carrier, hydroxylpropylmethylcellulose acetate succinate (HMPC AS) (Mehuys et al., 2005a). Changes of drug release were reported with PVAP capsules after one month storage at 25 ^oC / 75% RH and 25 ^oC / 60% RH, respectively.

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In contrast, Ghebremeskel et al. (2006) demonstrated that the addition of surfactant did not change the performance of extrudate as indicated by the indiscernible change in drug release profile after 6 month storage in accelerated humidity condition (Ghebremeskel et al., 2006). The authors suggested that recrystallization of the formulations were primarily determined by the polymer carrier rather than other additives, namely surfactant in this case.

Chapter 1.4.2.2.4 describes the possibility of lipid addition to HME products. A more recent investigation has shown that addition of lipid could preserve the physical stability of the solid dispersion product (Unga et al., 2010). This research group demonstrated the influence of lipid in the process of folding and unfolding of polyethylene glycol (PEG 4000), where lipid has shown to form a continuous single phase system with PEG and affect the folding of PEG polymeric chain. In order to effectively retard the unfolding of PEG, Unga et al. (2010) suggested that the lipid molecule should be large, branched and possess a small portion of polar surface. Among the tested lipid systems, tristearin was identified to be the best lipid component in preventing the unfolding process of PEG (Unga et al., 2010). Therefore, a good physical stability of HME product could be obtained by incorporating lipid components.

Storage Temperature

Storage temperature is another important factor in determining physical stability of a SD system. A low storage temperature (T < Tg of the system) could lead to better stability of a SD product due to the reduce molecular mobility of the extrudates (Hancock and Zografi, 1997). On the other hand, storage of formulation at temperature higher than the Tg of product can lead to an increase in polymer ductility and transforms into its rubbery state which unfold the polymeric chain.

Eventually, recrystallization occurred due to the rearrangement of drug molecules as a result of the increase in chain ductility of the polymer (Prodduturi et al., 2007).

Besides, the storage temperature has also reported to affect the physical structure of polymeric chain. PEO was reported to be in a meta-stable folded state after treatment of thermal and high shear processing as indicated by the reduction of melting temperature (Tm) (Prodduturi et al., 2005, Prodduturi et al., 2007, Mididoddi and Repka, 2007). However, these meta-stable folded chains can unfold into its stable form at a particular storage temperature of the extrudates. Crowley et al.

(2002) demonstrated that storage of PEO (a mixture of amorphous and crystalline polymer) at temperature lower than its Tm can cause degradation of the amorphous fraction of PEO, however, storage at higher temperature than Tm can cause oxidative degradation in both the amorphous and crystallites fractions of PEO (Crowley et al., 2002b).

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