ORIGINAL ARTICLES Ortofarma – Quality Control Laboratories, Matias Barbosa, MG, Brazil Compatibility of cholecalciferol, haloperidol, imipramine hydrochlo- ride, levodopa/carbidopa, lorazepam, minocycline hydrochloride, tacro- limus monohydrate, terbinafine, tramadol hydrochloride and valsartan in SyrSpend® SF PH4 oral suspensions H. C. POLONINI, S. L. SILVA, C. N. CUNHA, M. A. F. BRANDÃO, A. O. FERREIRA Received October 21, 2015, accepted December 2, 2015 Ortofarma – Quality Control Laboratories, BR 040, n. 39, Empresarial Park Sul. 36120-000. Matias Barbosa – MG. Brazil [email protected] Pharmazie 71: 185–191 (2016) doi: 10.1691/ph.2016.5177 A challenge with compounding oral liquid formulations is the limited availability of data to support the physical, chemical and microbiological stability of the formulation. This poses a patient safety concern and a risk for medication errors. The objective of this study was to evaluate the compatibility of the following active pharma- ceutical ingredients (APIs) in 10 oral suspensions, using SyrSpend® SF PH4 (liquid) as the suspending vehicle: cholecalciferol 50,000 IU/mL, haloperidol 0.5 mg/mL, imipramine hydrochloride 5.0 mg/mL, levodopa/carbidopa 5.0/1.25 mg/mL, lorazepam 1.0 mg/mL, minocycline hydrochloride 10.0 mg/mL, tacrolimus monohydrate 1.0 mg/ mL, terbinafine 25.0 mg/mL, tramadol hydrochloride 10.0 mg/mL and valsartan 4.0 mg/mL. The suspensions were stored both refrigerated (2 - 8 °C) and at controlled room temperature (20 - 25 °C). This is the first stability study for these APIs in SyrSpend® SF PH4 (liquid). Further, the stability of haloperidol,iImipramine hydrochloride, minocycline, and valsartan in oral suspension has not been previously reported in the literature. Compatibility was assessed by measuring percent recovery at varying time points throughout a 90 days period. Quantification of the APIs was performed by high performance liquid chromatography (HPLC-UV). Given the percentage of recovery of the APIs within the suspensions, the beyond-use date of the final preparations was found to be at least 90 days for most suspensions both refrigerated and at room temperature. Exceptions were: Minocycline hydrochloride at both storage temperatures (60 days), levodopa/carbidopa at room temperature (30 days), and lorazepam at room temperature (60 days). This suggests that compounded suspensions of APIs from different pharmacological classes in SyrSpend® SF PH4 (liquid) are stable. 1. Introduction in Table 1, compounded at a single concentration in SyrSpend® SF Extemporaneous preparation of oral liquid dosage forms is a PH4 (liquid) and stored both refrigerated and at room temperature. ® common and important pharmacy practice for patients that require SyrSpend SF is an internationally available, GMP produced, non-standard doses, experience swallowing difficulties or receive ready-to-use taste-masking oral liquid vehicle. Its suspending medication via enteral feeding tubes (Glass and Haywood 2006). properties are derived from starch without traditionally used excip- Oral liquids are not only common practice in pediatrics (Brion et ients that can have toxicological effects, induce allergic reactions al. 2003; Schirm et al. 2003), but also in the general adult popu- or cause irritation, such as sugar (Hill et al. 1988; Jijo and Flow- lation, where recent studies have demonstrated that up to 22.4 % erlet 2014), ethanol (Zuccotti and Fabiano 2014; Fiocchi et al. have difficulties swallowing (Lau et al. 2015; Marquis et al. 2013). 1999), propylene glycol (Committee on Drugs 1997; Fabiano et Oral liquids are relatively quick and easy to prepare with limited al. 2011), sorbitol (Johnston et al. 1994; Payne et al. 1997), benzyl need for compounding equipment and they allow for flexibility in alcohol (Gershanik et al. 1982; Centers for Disease Control 1982; dosage out of a single strength preparation (Brion et al. 2003). Committee on Fetus and Newborn 1983) and common food aller- The main challenge with compounding oral liquid formulations gens (Sakai et al. 2012; Audicana Berasategui et al. 2011). The is the limited availability of data to support the physical, chem- compatibility of SyrSpend® SF with various APIs has already ical and microbiological stability of the formulations (Glass and been demonstrated (Geiger et al. 2012a, 2012b, 2013a, 2013b, Haywood 2006; Brion et al. 2003; Conroy 2003). In a UK survey 2015; Sorenson et al. 2012; Sorenson and Whaley 2012; Voudrie it was found that in more than half (54 %) of the extemporaneous and Allen 2010; Voudrie et al. 2011; Vu et al. 2008; Whaley et al. formulations shelf-life was inadequately supported (Brion et al. 2012a, 2012b; Ferreira et al. 2015). 2003). Due to the limited availability of scientific data, there is little In this study the combined physical-chemical compatibility is harmonization in the concentration or formulation of compounded assessed, as a deficit in either of the two would result in an out oral liquids (Brion et al. 2003; Rood et al. 2014). This poses a of specification during analysis. The concentration for each API patient safety concern and a risk for medication errors (Rood et studied was selected based on commonly prescribed concentra- al. 2014). Demands have been made to publish scientifically veri- tions for children or adults. To the best of the authors’ knowledge, fied, palatable extemporaneous formulations with standardized there is no previous stability study in the literature for haloper- oral liquid concentrations to increase patient safety and adherence idol, imipramine hydrochloride, minocycline hydrochloride and (Brion et al. 2003; Conroy 2003; Rood et al. 2014; Allen 2008). valsartan oral suspensions. No stability studies of the current APIs The objective of this study was to evaluate the physical and chem- compounded in SyrSpend® SF PH4 (liquid) have previously been ical stabilities of the active pharmaceutical ingredients (APIs) listed published. Pharmazie 71 (2016) 185 ORIGINAL ARTICLES Table 1: Concentrations of the suspensions used in the study all conditions. Cholecalciferol and lorazepam decomposed under all stress conditions. After these validations, the stability of the API Concentration Action and use ® in suspension APIs in SyrSpend SF PH4 (liquid) was assessed. In this study we did not evaluate the uniformity of the drug in the Cholecalciferol (vitamin D3) 50,000 IU/mL Vitamin D analogue suspension, and expect that any non-soluble drug will exist as insol- Haloperidol 0.5 mg/mL Dopamine receptor antag- uble crystals, particulates, or precipitate. According to the Merck onist; neuroleptic Index 14th edition (2006), these are the solubilities of the APIs in Imipramine hydrochloride 5.0 mg/mL Monoamine reuptake water (major component of the used suspending vehicle): Cholecal- inhibitor; tricyclic antide- ciferol – practically insoluble; haloperidol – 1.4 mg/100mL; imip- pressant ramine hydrochloride – freely soluble; levodopa – 66 mg/40 mL; Levodopa/carbidopa 5.0/1.25 mg/mL Treatment of Parkinson’s lorazepam – 0.08 mg/mL; tacrolimus monohydrate – insoluble disease in water; terbinafine – slightly soluble; tramadol hydrochloride – soluble; and valsartan – soluble. Therefore, we predict that some Lorazepam 1.0 mg/mL Benzodiazepine heterogeneity of drug distribution will exist for cholecalciferol, Minocycline hydrochloride 10.0 mg/mL Tetracycline antibacterial levodopa, lorazepam and tacrolimus monohydrate in the stored Tacrolimus monohydrate 1.0 mg/mL Immunosuppressant suspensions and that unsufficient mixing prior to sampling may Terbinafine 25.0 mg/mL Antifungal lead to increased variance in API percentage recovery. The stability results are shown in Table 5 and are expressed as Tramadol hydrochloride 10.0 mg/mL Opioid receptor agonist; noradrenaline reuptake relative percent of recovery (initial sampling time = 100 %). For inhibitor; analgesic the suspensions to be considered stable, the relative percentage recovery should lie within 90-110 % (USP 2015; BP 2015; EP Valsartan 4.0 mg/mL Angiotensin II (AT ) 1 2015). Figure 1 graphically represents the stability of the APIs in receptor antagonist SyrSpend® SF PH4 (liquid) in terms of absolute nominal concen- tration. 2. Investigations, results and discussion At each sampling time, the visual appearance of the suspensions Validation studies of all methods of analysis (chromatographic was evaluated to verify their homogeneity and physical stability (data not shown). Throughout the whole study, no phenomena such conditions described in Table 2) were performed and all results as precipitation, turbidity, macroscopically visible crystal growth, (Table 3) met the respective acceptance criteria. Stability-indi- odor generation, phase separation, flocculation or caking were cating studies were also conducted. These results are summarized observed, except for minocycline hydrochloride after 60 days of in Table 4. Stability-indicating studies are important to determine storage. No study on the stability of minocycline hydrochloride in if the used methods are fully validated and adequate to identify oral liquids was found, but the Merck Index (2006) states that this decomposition of the APIs by chromatographic analysis. The API is sensitive to light and to surface oxidation (also confirmed in decomposition profile of the APIs notably varied for different our findings in Table 4). As all suspensions were stored in light-re- stressing conditions. Only levodopa was found to be stable under sistant bottles, it is likely that the decomposition