Introduction
Aneurysmal subarachnoid hemorrhage (aSAH) is a critical neurological emergency, accounting for approximately 5% of all strokes. It occurs when a cerebral aneurysm ruptures, leading to the accumulation of blood within the subarachnoid space. Despite its relatively low incidence, aSAH carries a disproportionately high mortality rate of 30%–50%. This high mortality is frequently driven not by the initial rupture, but by secondary complications such as vasospasm and delayed cerebral ischemia (DCI). Furthermore, a significant majority of survivors suffer from long-term neurological deficits, contributing to a substantial socioeconomic burden [1–7]. To mitigate these risks, clinical guidelines mandate the prophylactic administration of nimodipine (60 mg orally every 4 h for 21 days post-ictus). Notably, nimodipine remains the only approved pharmacological intervention proven to improve clinical outcomes in this patient population [4, 5].
Nimodipine, a 1, 4-dihydropyridine calcium channel blocker, exerts its action through inhibiting L-type voltage gated calcium channels found in the cerebral blood vessels smooth muscles, hindering the calcium ions influx leading to vasodilation [8–12]. Although the exact neuroprotective mechanism of nimodipine is not fully known to date, nimodipine is suggested to have neuroprotective pathways through endogenous fibrinolytic activity, attenuation of cortical spreading depolarization and anti-inflammatory properties [4, 5, 12–14].
The clinical utility of nimodipine is frequently complicated by significant pharmacokinetic (PK) variability. Research has demonstrated that this erratic PK behavior leads to inconsistent patient outcomes, making it difficult to establish a definitive correlation between drug exposure and therapeutic success [15–19]. While patient-specific covariates, such as age, sex, race, and genetic predisposition, contribute to this variability, drug formulation and administration techniques are increasingly recognized as pivotal factors potentially impacting clinical efficacy [12]. This is particularly problematic in regions with limited formulation options. For instance, in Canada, nimodipine is primarily available only as tablets (Nimotop®, Laboratoire X.O), whereas other markets, such as the USA, utilize soft gelatin capsules and oral solutions. Therefore, clinicians are left with few alternatives for patients who cannot swallow, particularly in countries where manufactured oral solutions of nimodipine are not available commercially [12, 20].
In clinical practice, tablets are frequently crushed in water and administered via feeding tubes for unconscious or dysphagic patients. However, evidence suggests this practice is suboptimal; studies indicate that crushed tablet administration may be associated with a higher prevalence of moderate-to-severe vasospasm and DCI [20–22]. In addition, the manufacturer recommends against crushing nimodipine tablets [23]. Consequently, there is a need for alternative formulations or novel delivery methods to ensure safe and equitable nimodipine administration in countries where oral tablets are the only available option.
The aim of this study was to develop and evaluate the stability of an extemporaneously prepared nimodipine suspension. This approach may serve as a suitable substitute for nimodipine tablets in patients who are unable to ingest the entire tablet, overcoming problems associated with the administration of crushed nimodipine tablet dispersion in water. Also, it can be a potential step towards standardizing the institutional practices and reducing the number of factors accounting for pharmacotherapy variability in aSAH patients.
Discussion
The limited availability of enteral nimodipine dosage forms in Canada poses significant administration challenges for unconscious, dysphagic and ventilated patients [22]. Although the manufacturer advises against crushing nimodipine tablets due to compromised bioavailability [23], this practice remains the only option for enteral administration via feeding tubes in this patient population. However, dispersing crushed nimodipine tablets in water and feeding tube administration has been associated with potentially poorer clinical outcomes, including increased rates of vasospasm and DCI [15, 16, 18, 21, 22]. Furthermore, while an intravenous (IV) formulation is available in Europe, Australia, and China, its clinical utility is hindered by the high ethanol content (∼23.7% v/v). This can cause vascular irritation, phlebitis, and injection-site reactions, alongside an inherent risk of hypotensive crises, which ultimately led to its discontinuation in North America [35–37]. Additionally, the IV route has demonstrated equivalence to the oral route [37], aligning with findings from Soppi et al. [38] and Kronvall et al. who reported no significant differences in clinical outcomes between parenteral and enteral administration [39]. Soppi et al. compared Nimotop® IV infusion to enteral administration of tablets (two 30 mg Nimotop® tablets), crushed in 1% hypromellose for unconscious or ventilated patients [38]. Similarly, Kronvall et al. compared Nimotop® whole tablets or crushed tablets suspended in water to Nimotop® IV infusion [39]. Given the need for a safe, effective, and convenient enteral option, this study aimed to formulate an extemporaneous oral nimodipine suspension and systematically evaluate its stability.
The reason behind choosing suspension as our dosage form is because tablet is the only dosage form available in Canada [22]. Also, nimodipine’s high lipophilicity renders it practically insoluble in water [23] and formulating it as a solution using high organic solvent already exists in the USA market (Nymalize®, Azurity Pharmaceuticals, Inc.). The high polyethylene glycol (PEG) 400 content in these solution forms has cathartic-like effect that causes side effects such as diarrhea [22, 40, 41]. McElhiney et al. tried compounding nimodipine as oil-based suspension, but it did not work either due to stability issues, or adverse effects such as diarrhea [42].
Although ORA-Plus® and ORA-Sweet® are standard vehicles for extemporaneous compounding in hospital settings, to our knowledge, there is no report of their use in making compounded nimodipine suspensions. Vehicle choice plays a critical role in gastrointestinal (GI) tolerance, particularly during intensive 21-day treatment courses. Hyperosmolar liquid vehicles, including vehicle systems containing high concentrations of sorbitol or sugar-based syrups like Ora-Sweet, have been identified as potential osmotic cathartics capable of inducing diarrhea in enterally fed patients [43]. However, in our formulation, Ora-Sweet is blended in a 1:1 ratio with Ora-Plus, a vehicle characterized by a low osmolality (157 mOsm/kg) [24]. This equal-part combination substantially dilutes the hyperosmolar burden of the final vehicle system. Under standard clinical dosing (60 mg nimodipine every 4 h, or 60 mL/day of a 6 mg/mL suspension), a patient receives a cumulative volume of only 30 mL/day of Ora-Sweet. Additionally, compounding with sugar-free alternatives such as Ora-Sweet SF, which possesses roughly half the osmolality of standard Ora-Sweet, offers an established strategy to further reduce overall osmolality when combined 1:1 with Ora-Plus [44]. So, we selected this 1:1 vehicle combination to facilitate the seamless translation of our formulation into clinical practice, given the availability of both vehicles and acceptable viscosity of the 1:1 ratio of the two vehicles for administration through feeding tubes. Furthermore, equivalent volumes of ORA-Plus® and ORA-Sweet® have demonstrated established stability for other extemporaneous preparations, including a mycophenolate mofetil suspension [45] and a suspension of nifedipine, a structurally related calcium channel blocker [46]; both remained stable for up to 3 months under refrigerated and room-temperature conditions. These precedents strongly supported the use of this vehicle ratio for compounding nimodipine.
While numerous studies have utilized HPLC for nimodipine assays in various formulations and biological matrices [26, 47, 48], our analytical approach was specifically adapted from Shang et al., who successfully employed HPLC to quantify nimodipine in tablets [26]. This method was validated within our laboratory, demonstrating linearity over a concentration range of 10–100 μg/mL. The assay also exhibited excellent selectivity, with no interfering peaks observed at the retention time of the analyte. Furthermore, the method demonstrated acceptable intra-day and inter-day precision and accuracy adhering to the EMA guidelines acceptance criteria [27]. Forced degradation studies were conducted using stress conditions (acidic, alkaline, and oxidative) to verify that the analytical peak corresponded exclusively to intact nimodipine [28–30].
Our compounded nimodipine suspension maintained chemical stability, defined as retaining 90%–110% of the baseline concentration, for 3 weeks under FT and 4 weeks at RT using a light resistant container for the formulation. We clarify that the one-week shorter stability duration under FT storage conditions was ascribed to a higher rate of solvent evaporation, leading to apparent hyper-concentration, rather than chemical degradation. FT storage environments maintain low relative humidity; combined with repeated opening of the samples for periodic sampling, this promotes gradual water loss, leading to hyper-concentration, agreeing with literature [49, 50].While this study evaluated stability over a one-month duration, this timeframe is clinically sufficient given that the standard treatment course for nimodipine is strictly 21 days. Additionally, based on the standard dosing regimen of 60 mg every 4 h [4, 5], a 250 mL bottle would be depleted in 4 days, which falls well within our proven stability window. In contrast, the dispersion of nimodipine tablets in water fell outside the acceptable 90–110% cutoff, suggesting the inhomogeneity of the tablet dispersion in water. Conversely, our novel suspension recovery was consistently within the acceptable window for 3 weeks for FT storage and 4 weeks for RT storage, highlighting the superior stabilizing properties of ORA-Plus® and ORA-Sweet® vehicles in maintaining a homogenous suspension. Clinically, the flavoring agents in ORA-Sweet® offer a significant palatability advantage over a simple crude tablet dispersion in water, and the availability of ORA-Sweet SF® provides an equivalent option for diabetic patients [25]. Altogether, these findings work together justifying why the compounded suspension is deemed a convenient and feasible clinical alternative to the current practice of dispersing the drug in water.
The compounded suspension maintained physical stability throughout the four-week study, exhibiting no changes in color or odor. It retained its yellowish tinge with faint berry odor characteristic of the ORA-Sweet® vehicle [25]. Additionally, the compounded suspension maintained a highly stable mean pH of 4.34 ± 0.04 from baseline to the final day of the study, regardless of storage conditions. This stability is attributed to the buffering system (citric acid/sodium phosphate) present in the suspending agents, which maintains the pH within a narrow range of 4–4.5 [24, 25]. In contrast, the pH of the crude tablet dispersion in water fluctuated significantly over a wider range (5.42–6.47, p < 0.001). This was evident in the pH trajectory for the tablet dispersion in water under FT storage (Table 4). Unlike our novel suspension, the crude tablet dispersion lacks any buffering capacity, rendering this system liable for pH drifts. Under FT storage, the initial lower pH was most likely due to the high solubility of carbon dioxide gas at cold temperatures. Periodic opening of the bottles for sampling promoted degassing of carbon dioxide, alongside the temperature-mediated dissolution of the tablet excipients and accumulation of the excipients by day 28, led to an upward pH shift [51, 52]. These changes showcase the necessity of having a buffered structured vehicle for extemporaneous preparations to avoid the inherent instability of the crude dispersions.
Additionally, the compounded suspension demonstrated superior homogeneity and particle distribution. This was supported by a more negative mean ZP of −21.43 ± 1.89 mV, compared to −8.42 ± 2.28 mV for the comparator prepared following dispersion of crushed nimodipine tablets in water (p < 0.001). This highly negative ZP, an inherent feature of the formulation that did not require the external addition of electrostatic stabilizers, remained consistent over the four-week duration of the study. Furthermore, the sedimentation volume (F) results indicated that the compounded suspension have a significantly higher mean F value (0.99 ± 0.01) than the crude tablet dispersion in water (0.26 ± 0.04, p < 0.001), reflecting the formation of a more flocculated suspension in nimodipine suspension prepared using ORA-Plus®/ORA-Sweet® vehicles. The higher sedimentation volume of this formulation implies better dispersity during storage which is attributed to the presence of flocculating agents in the ORA-Plus® vehicle [24].
Particle size characterization was conducted to monitor physical appearance and assess potential crystal growth or aggregation during storage. While Dynamic Light Scattering (DLS) is the standard method for sub-micron particles with regular or spherical geometry, it was unsuitable for our formulation. As outlined in ISO 22412:2017, DLS is optimized for sub-micrometer systems where Brownian motion dominates. For particles exceeding 1µm, gravitational sedimentation prevails over thermal diffusion, breaching a core principle of DLS theory [53, 54]. Furthermore, our compounded formulations contain highly irregular, polydisperse particles (Figure 4). In such polydisperse systems, larger coarse particles induce severe intensity bias by masking scattering signals from smaller fragments, leading to artificially elevated polydispersity indices, a phenomenon observed during our preliminary testing. Consequently, optical microscopy paired with ImageJ digital software analysis was utilized as a direct, morphology-based alternative. Particle dimensions were quantified as two-dimensional surface areas, which more accurately represent irregular, non-spherical fragments than hydrodynamic diameter assumptions. A total of approximately 550 individual particles were analyzed across four weekly time points. No statistically significant changes in particle surface area were observed over the 4-week storage period (p > 0.05), reflecting the consistent comminution achieved by uniform manual compounding procedures. Nevertheless, we acknowledge that optical microscopy represents a semi-quantitative approach constrained by 2D area projections and lower sampling throughput compared to ensemble methods like laser diffraction. Future evaluations could benefit from advanced 3D automated image analysis or static laser diffraction designed for coarse, polydisperse suspensions.
Nimodipine is known to exist in two polymorphs; modification I is the commercial metastable racemate polymorph, while modification II is the stable conglomerate polymorph [55, 56]. According to Grunenberg et al., both modifications are enantiotropic; capable of undergoing transformations based on temperature [56]. FT storage could lead to supersaturation and polymorphic transitions, secondary to solvent evaporation [49, 55, 56]. Additionally, modification I tends to be seen as coarse chunks that grow into plates. On the other hand, modification II tends to be in the form of more homogenous circular aggregates [55–57]. Based on the coarse irregular particles seen through our microscopy findings (Figure 4) and the precedent description of Grunenberg et al. [56] and Cardoso et al. [55], it could be tentatively said that the observed particles were in modification I form. However, this needs to be confirmed using specialized techniques such as differential scattering calorimetry, X-ray diffraction and dissolution methods [55–57]. It is not clear however if the bioavailability of nimodipine would change with changing forms. Therefore, it is prudent to evaluate the formulation’s bioavailability prior to implementation.
Viscosity was evaluated exclusively for the compounded suspension to characterize its flow behavior. As expected, the suspension demonstrated shear-thinning behavior across a shear rate range of 0.1–1000 s-1, which is attributable to the viscosity inducing agents used in the ORA-Plus® [24]. According to Mezger, shear rates between 10-2 s-1 and 10-1 s-1 simulate low-shear conditions where particles undergo sedimentation or levelling. Increasing the shear rate to 101 s-1 simulates gentle shaking, while 102 s-1 represents vigorous mixing [58]. The National Dysphagia Diet (NDD) utilizes a shear rate of 50 s-1 as a benchmark for classifying liquid viscosity [59, 60]. At baseline (shear rate of 47.44 s-1), the apparent viscosity of the compounded suspension was 0.200 Pa. s (200 mPa. s) at FT and 0.143 Pa. s (143 mPa. s) at RT. These values classify the suspension within the “nectar-thick” range. However, by day 28, the apparent viscosities at this same shear rate increased to 1.44 Pa. s (1440 mPa. s) and 1.16 Pa. s (1160 mPa. s) for FT and RT, respectively, shifting the suspension into the “honey-thick” classification. This indicates a time-dependent increase in viscosity, particularly under refrigeration. Ultimately, the high viscosity at low shear rates (<10-1 s-1) suggests robust stability against sedimentation at rest, which is consistent with the high F values observed. Conversely, the decreased viscosity at higher shear rates (100-101 s-1) ensures the suspension remains easy to pour and administer.
Building upon the favorable flow characteristics established in the previous section, we evaluated the practical administration of the compounded suspension through two common feeding tubes: Salem Sump™ polyvinyl chloride (PVC) tubes and Corflo® Nasogastric/Nasointestinal ENFit® tubes. To our knowledge, these represent the standard tubes utilized in the hospitals, and no prior studies have investigated nimodipine administration using these specific models. The compounded nimodipine suspension was administered through two lines of each tube type using a six-replicate cycle of injection followed by flushing. Throughout this procedure, all lines maintained full patency with no observed occlusions. Visually, the second 10 mL water flush was notably clearer than the initial 10 mL flush. Consequently, to ensure complete clearance of the suspension, we recommend a minimum flush volume of 20 mL of tap water following dose administration for either tube type.
Given that the tubes maintained their patency without occlusion, we subsequently evaluated the potential for drug adsorption to the feeding tube walls to verify that the dose was effectively delivered without significant loss. Both tube types yielded an average nimodipine recovery exceeding 98%, confirming that no clinically significant drug adherence occurred. Although, nimodipine is known to adsorb to PVC [35], a primary component of the Salem Sump tubes, no major drug loss was detected in this study. This discrepancy can likely be attributed to formulation differences, as the interactions reported in the literature specifically involved the IV formulation of nimodipine [35]. Furthermore, contact time is a critical variable; an infused IV solution is exposed to PVC tubing for a substantially longer duration than an enteral dose pushed rapidly through a feeding tube. Finally, specific tube manufacturing variations and overall PVC content may also influence the extent of adsorption.
In clinical practice, enteral feeding tubes are frequently used to deliver complex enteral nutrition (EN) formulas alongside pharmacotherapy. These nutritional formulations contain diverse lipids, proteins, carbohydrates, and electrolytes that may physically or chemically interact with suspended drug particles. Although physical compatibility with liquid EN formulas was not directly evaluated in the present study, existing clinical literature provides relevant context regarding nimodipine’s interaction with food. According to the reference product monograph, food co-administration alters nimodipine’s absorption kinetics by reducing peak plasma concentrations (Cmax) by approximately 40% and doubling time to reach peak plasma concentrations (Tmax), while leaving the total extent of absorption (AUC) largely unaffected [23]. However, these historical data were established using conventional whole tablets rather than compounded oral liquid suspensions. Consequently, how physical mixing with liquid EN formulas within the narrow lumen of a feeding tube affects particle aggregation, drug solubility, or tube patency requires dedicated investigation.
The reported association between crushed nimodipine tablets and poorer clinical outcomes may, at least in part, stem from physical delivery failure rather than tablet crushing itself. Nimodipine is a highly lipophilic, BCS Class II molecule with minimal aqueous solubility [61]. When tablets are crushed in water at the bedside, the resulting dispersion is an unstable, deflocculated slurry. Lacking suspending agents, viscosity modifiers, or adequate surface charge, the particles undergo rapid, immediate sedimentation, reaching minimum sedimentation volume on the day of preparation, while suffering significant drug loss to mortar, pestle, and syringe surfaces. Furthermore, unstandardized bedside crushing exposes photolabile nimodipine to ambient ICU light during variable preparation delays, promoting photolytic degradation. These physical barriers lead to unpredictable dosing. Because crushed tablets represent the sole starting material in jurisdictions where oral solutions are unmarketed, utilizing a structured vehicle system (1:1 ORA-Plus/ORA-Sweet) directly addresses these delivery failures. The thixotropic network of ORA-Plus maintains homogeneous particle suspension at rest to ensure uniform volumetric dosing, while its higher negative ZP suppresses particle agglomeration and enteral line adhesion. Crucially, standardizing preparation in the pharmacy, clinicians can mitigate the risks associated with prolonged lag times and bright ICU lighting, ensuring the patient receives a potent, non-degraded dose. Although observational clinical data link crushed tablets to adverse outcomes, stabilizing the physicochemical platform is a mandatory prerequisite for achieving reliable therapeutic drug delivery.
Although utilizing pharmaceutical-grade pure nimodipine powder represents a theoretical alternative to avoid tablet crushing, this approach is operationally and clinically unfeasible for hospital compounding. Bulk raw powder is expensive, unavailable through standard hospital supply chains, and presents significant handling challenges. Physically, pure nimodipine is cohesive and electrostatic, requiring pre-formulation additives (such as glidants and flow modifiers) to overcome severe surface adhesion and clumping. Furthermore, bulk weighing introduces substantial risks of dosing errors compared to using pre-formulated commercial tablets and increases light-induced degradation due to a high exposed surface area. Consequently, utilizing commercially available tablets provides a safe, pragmatic, and reproducible starting material for extemporaneous compounding in clinical practice.
ORA-Blend® is a commercial, pre-mixed 1:1 mixture ORA-Sweet® and ORA-Plus®, containing the same preservatives, pH modifiers, suspending agents, and is also marketed in a SF version [62]. Although this vehicle would facilitate extemporaneous compounding by reducing preparation time and volumetric measurement errors, we chose to adopt the equivalent ratios of ORA-Sweet® and ORA-Plus®, mimicking their previous application with another calcium channel blocker, nifedipine [46]. We speculate that our physicochemical findings, thixotropic behavior and feeding tube compatibility can be extrapolated to the ORA-Blend® vehicle without compromising the stability profile of the developed suspension.
This study has limitations. First, the formulation was evaluated strictly in vitro. Future in vivo safety and pharmacokinetic studies are necessary to determine how gastrointestinal motility, enzymatic activity, and hepatic first-pass metabolism impact the bioavailability of this specific suspension. Another limitation of this study is the absence of a comparator group using the commercially available FDA-approved nimodipine oral solution. Because this formulation is not currently marketed or readily procurable in Canada, its inclusion was not feasible. Consequently, direct benchmarking against an established reference standard with known bioavailability and clinical efficacy data was not performed. Additionally, while drug loss to the enteral feeding tube walls was negligible and tube patency was successfully maintained in our administration model, these findings are derived from a single-dose simulation. Consequently, these results cannot be definitively extrapolated to extended 21-day clinical treatment regimens, where cumulative drug adsorption or gradual lumen occlusion could theoretically occur over repeated dosing cycles. In clinical practice, this risk is largely mitigated by standardized administration protocols that dictate thorough water flushes before and after each dose, as well as institutional schedules for routine tube replacement. Nevertheless, the absence of a continuous 21-day multi-dose simulation remains a study limitation. Extended compatibility and accumulation assessments over the full treatment duration should be incorporated into future prospective and bioavailability investigations. Furthermore, while our vehicle system (1:1 Ora-Plus:Ora-Sweet) was designed to minimize hyperosmolar exposure relative to PEG-400-based commercial solutions, the gastrointestinal tolerability of this formulation was not formally evaluated in vivo. Given that nimodipine therapy requires an intensive 21-day administration regimen in critically ill patients, osmotic catharsis and diarrhea remain theoretical risks that could disrupt patient management. In vitro osmolality profiles and vehicle dilution strategies cannot definitively establish clinical safety or gut comfort over extended therapy. Consequently, formal clinical evaluations assessing gastrointestinal tolerability across the full 21-day treatment duration represent a necessary next step prior to routine clinical adoption. Finally, a notable limitation of this study is that physical compatibility with commercial enteral nutrition (EN) formulas was not assessed. Because EN formulas contain complex macromolecular matrices that could potentially induce drug precipitation, alter suspension viscosity, or cause physical tube blockage, co-administration compatibility remains to be fully verified. Building upon the baseline stability established in this work, future research should follow a structured progression: first, evaluating in vitro physical and chemical compatibility (e.g., precipitation, binding, and flow dynamics) during simulated co-administration with various commercial EN formulas; second, conducting extended multi-dose compatibility evaluations over full treatment durations; and ultimately, executing formal in vivo bioavailability and pharmacokinetic studies.