Next Article in Journal
Hydroxytyrosol: A Promising Therapeutic Agent for Mitigating Inflammation and Apoptosis
Previous Article in Journal
Exploring 3D Printing in Drug Development: Assessing the Potential of Advanced Melt Drop Deposition Technology for Solubility Enhancement by Creation of Amorphous Solid Dispersions
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Pharmaceutics
Volume 16
Issue 12
10.3390/pharmaceutics16121502
pharmaceutics-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Investigating Strategies to Enhance the Aqueous Solubility of Ketamine HCl for Intranasal Delivery

by
Sourour Idoudi
1,
Alaaeldin Saleh
2,
Mohammed Akkbik
1,3,
Leena Amine
4,
Khalid Alansari
4,
Ousama Rachid
1 and
Alaaldin M. Alkilany
1,*
1
Department of Pharmaceutical Sciences, College of Pharmacy, Qatar University, Doha P.O. Box 2713, Qatar
2
College of Medicine, Qatar University, Doha P.O. Box 2713, Qatar
3
Central Laboratories Unit, Office of VP for Research & Graduate Studies, Qatar University, Doha P.O. Box 2713, Qatar
4
Department of Emergency, Sidra Medicine, Doha P.O. Box 26999, Qatar
*
Author to whom correspondence should be addressed.
Pharmaceutics 2024, 16(12), 1502; https://doi.org/10.3390/pharmaceutics16121502
Submission received: 15 October 2024 / Revised: 12 November 2024 / Accepted: 17 November 2024 / Published: 22 November 2024
(This article belongs to the Section Physical Pharmacy and Formulation)
Browse Figures
Versions Notes

Abstract

:
Background: Ketamine HCl, an FDA-approved therapeutic, is administered through various routes, including intranasal delivery. Administering an adequate therapeutic dose of intranasal ketamine HCl is challenging due to the limited volume that can be delivered intranasally given the current commercially available concentrations. Objectives: This study investigates solubilizing strategies to enhance the aqueous solubility of ketamine HCl for intranasal administration. Methods: We assessed the solubility profile of ketamine HCl by evaluating factors such as pH, co-solvents, and surfactants. Additionally, we developed and validated a UV-Vis spectroscopy method for ketamine HCl analysis. Results: Our solubility screening in various organic co-solvents revealed the following order of effectiveness in enhancing solubility: methanol > water > propylene glycol > ethanol > dimethyl sulfoxide (DMSO) > N-methyl-2-pyrrolidone (NMP). Despite methanol’s superior solubility, its potential toxicity, coupled with the relatively lower effectiveness of other solvents compared to water, suggests that a co-solvency approach is not advantageous for ketamine HCl. We found that ketamine HCl solubility increased with medium acidity, with pH 3.5 being the optimal for further formulation studies. The impact of pharmaceutical surfactants on ketamine HCl solubility at an acidic pH was also evaluated. Surfactants tested included SDS, PEG 400, PVP, Tween 20, poloxamer 188, and lecithin. Notably, PEG 400 and PVP reduced solubility due to a salting-out effect, whereas Tween 80, lecithin, and poloxamer 188 slightly improved solubility through micelle formation. Among the surfactants tested, 1% SDS emerged as the most effective in enhancing ketamine HCl solubility. Conclusions: These outcomes highlight the potential of these solubilization strategies to address the solubility limitations of ketamine HCl, enabling the preparation of highly concentrated ketamine HCl formulations for intranasal delivery.

1. Introduction

In the 1950s, Parke-Davis industries initiated the search for an ideal anesthetic product with analgesic potential among the derivatives of phencyclidine drugs [1]. Among these trials, the synthesis of ketamine had emerged in the 1960s [2,3]. Ketamine, also named 2-O-chlorophenyl-2-methylamino cyclohexanone, is an approved pharmaceutical by the Food and Drug Administration (FDA) and possesses a chemical formula of C13H16ClNO [4]. Moreover, ketamine consists of a central chiral carbon, thus enabling two different steric configurations. Furthermore, ketamine is a racemic mixture that consists of equal amounts of two enantiomers, (S)-ketamine and (R)-ketamine (Figure 1) [5]. These two enantiomers have different affinities for different receptors, and consequently somewhat different clinical profiles [5,6,7]. For instance, the FDA approved an intranasal (S)-ketamine formulation (Spravato®) as an antidepressant drug in 2019 [8,9,10].
As a pharmaceutical, ketamine possesses versatile biomedical applications including procedural sedation and depression treatment, in addition to off-label uses such as asthma treatment and pain management [9,11,12,13]. Various administration routes, including intravenous (IV), intramuscular, sublingual, oral, and intranasal (IN) have been reported for ketamine [10,14]. Nowadays, IN drug delivery is becoming a potential alternative to other drug administration routes because the nasal cavity is highly supplied with blood vessels that facilitate the rapid absorption of drugs, leading to the enhanced bioavailability of the drug in the site of action in a non-invasive method [15,16]. Thus, the IN route offers a combination of rapid absorption, improved bioavailability, convenience, and the potential for both systemic and localized effects, making it a valuable option for drug delivery. However, variations in the administration route of ketamine might need dose adjustments to achieve the intended therapeutic effect [1,17,18]. For instance, the IN delivery of ketamine is mainly affected by the drug’s solubility, stability, and the pH of the administered dose [19]. Moreover, the nasal cavity has a limited volume capacity, where concentrated doses in a small volume ranging between 0.2 and 0.3 mL per nostril are considered the ideal volumes, whereas larger volumes would not be reliably absorbed due to mucosal surface saturation and runoff from the nasal cavity [20,21,22]. Usually, ketamine doses ranging from 3 to 5 mg/kg are used for mild sedation, and thus, it is necessery to solubilize 200–300 mg/mL of ketamine HCl, which exceeds its solubility limit [23,24]. In addition, in our ongoing interest to evaluate the sedative efficacy of an IN ketamine HCl formulation, we are planning to compare it to the standard IV ketamine HCl administration in patients, which requires a large quantity of ketamine HCl to be dissolved in a unit volume of medium suitable for IN delivery, prompting the investigation presented in this work.
There are several approaches to improving drug solubility and its IN delivery, including pH optimization as well as the incorporation of co-solvents or surfactants [25,26,27]. The choice of the solubilization approach could considerably affect the drug’s solubility, stability, and bioavailability in the site of action [28], as well as prevent its precipitation, degradation, and aggregation during storage [29,30]. The pH is a critical variable controlling the solubility of ionizable drugs, and this is the case with ketamine HCl, which is a weak base drug (pKa of 7.5) [31,32]. Various co-solvents can be used to improve a drug’s solubility, including methanol, ethanol, propylene glycol (PG), dimethyl sulfoxide (DMSO), dimethylformamide (DMF) and others. Pharmaceutical surfactants and solubilizing agents are abundant and range from molecular surfactants and polymeric surfactants to polymers and various types of nanovehicles. In addition, ketamine HCl is preferred for IN formulations due to its higher aqueous solubility, which is essential for its effective delivery through the nasal route. Unlike the free base, ketamine HCl dissolves readily in water, especially at acidic pH levels, making it suitable for the limited volume available for IN administration. It is also important to note that this salt form of ketamine is used in FDA-approved intravenous injections currently available on the market. The literature is abundant with reports detailing the enhancement of the solubility of various drugs using these solubilizing approaches; however, there are no such studies available for ketamine HCl. Furthermore, as ketamine HCl is a widely used therapeutic agent, it is crucial to develop and validate analytical methods for its quantification in pharmaceutical dosage forms. The literature reports methods such as high-performance liquid chromatography (HPLC), mass spectrometry (MS), and gas chromatography (GC), all of which require trained personnel, and significant time, cost, and effort. In contrast, Ultraviolet-Visible (UV-Vis) spectrophotometry is a simple and rapid method that allows for the reliable quantification of drugs [33,34,35]. In this regard, this study aims to investigate the following:
1.
Explore the solubility profile of ketamine HCl for IN delivery by manipulating different variables including pH, co-solvent addition, and incorporation of different surfactants with the goal of achieving an effective concentration within a small volume.
2.
Develop a validated method for the ketamine HCl analysis using UV-Vis spectrophotometry.

2. Material and Methods

2.1. Materials

Ketamine HCl was obtained from Supriya Lifescience Ltd., Mumbai, India. PG (CAS No. 57-55-6), poloxamer (PLX) 407 (CAS No. 9003-11-6), sodium dodecyl sulfate (SDS, CAS No. 151-21-3), DMSO (CAS No. 67-68-5), and polyethylene glycol (PEG) 400 (CAS No. 25322-68-3) were purchased from Sigma-Aldrich, St. Louis, MO, USA. PLX 188 (CAS No. 9003-11-6) was purchased from Glentham Life Sciences, Corsham, Wiltshire, UK. Polyvinylpyrrolidone (PVP, CAS No. 9003-39-8) was purchased from Thermo Fisher Scientific, Waltham, MA, USA. Tween 80 (CAS No. 500-019-9), ethanol, lecithin soya (LS, CAS No. 8030-76-0), and methanol were purchased from VWR, Radnor, PA, USA. Other chemicals and co-solvents used were reagent grade and used as directed.

2.2. UV-Vis Method Validation

A new method for ketamine HCl analysis using UV-Vis spectrophotometry was validated according to the International Conference on Harmonisation guidelines for the validation of analytical procedures [36,37].

2.2.1. Linearity

Linearity was investigated using ketamine HCl solution in 0.1 M citrate buffer (CB), pH = 3.5, in different concentrations levels (25, 50, 100, 200, 300, 400, and 500 µg/mL). The absorbance of calibration standards was measured using Jenway 7205 UV/Vis 72 Series Diode Array Scanning Spectrophotometer (Jenway, London, UK). UV–vis absorption spectra were recorded using 10-mm quartz cuvettes (Hellma, Müllheim, Germany) of a 1 cm optical path length. The spectrophotometric measurements were performed in triplicate in the range of 200–400 nm. The absorbance was further converted into concentration using the calibration curve of ketamine HCl. The linearity was evaluated using linear regression analysis to evaluate the standard error of intercept, standard error of slope, and correlation coefficient (R2).

2.2.2. Selectivity

Selectivity for ketamine HCl was investigated by assessing different blank samples, including different solvents (CB pH 3.5, CB pH 5.5, and phosphate-buffered saline (PBS) pH 7.5) and surfactants (1% SDS, 1% PLX 407, 1% PLX 188, and 1% PEG 400), for potential interference with the quantification of ketamine HCl. In brief, a stock of ketamine HCl (200 µg/mL) was prepared in each condition, followed by analysis in the range 200–400 nm, using a UV/Vis spectrophotometer as described in Section 2.2.1.

2.2.3. Precision

The precision of the method was evaluated using repeatability (intra-day) and intermediate precision (inter-day) at three concentration levels (25, 100, and 250 µg/mL) of ketamine HCl (n = 12). Repeatability was evaluated by evaluating different samples at the same concentration and on the same day. The intermediate precision was evaluated by comparing the same sample on different days (1 day, 2 days, and 1 week). Precision was reported as relative standard deviation (RSD) % expressed as follows: (SD/mean) × 100. Accuracy was reported as relative error (RE) % as follows: ∣(Measured Value − True Value)/True Value| × 100. The limit of detection (LOD) was assessed as follows: LOD = 3.3 × σ/S, where σ is the standard deviation of the y-intercept, and S is the slope of the calibration curve. The limit of quantification (LOQ) was calculated as follows: LOQ = 10 × σ/S.

2.2.4. Thermal Stability

The stability of the samples was assessed at three concentration levels (25, 100, and 250 µg/mL) of ketamine HCl on different days (1 day, 2 days, and 1 week). Samples were stored at 2 different conditions (at 4 °C and 25 °C). At each point, the absorbance was measured, and the concentration was calculated using the calibration curve equation. Data were expressed as the mean ± standard deviation (SD) (n = 6).

2.3. Solubility of Ketamine HCl in Various Solvents

Different solvents (i.e., water, methanol, ethanol, PG, DMSO, and NMP) were used to assess the solubility of ketamine HCl in each solvent. In brief, ketamine HCl was ground and added to a glass vial (500 mg/mL). The contents of the vials were then mixed using a vortex mixer to confirm the presence of any excess amount of ketamine HCl in each vial. Further, vials were attached to a temperature-controlled benchtop orbital shaker for shaking at 240 rpm at 25 °C for 14 h. After, the vial contents were centrifuged for 10 min at 6000× g. The obtained supernatant was separated, and the absorbance of each sample was measured in the range 200–400 nm, using a UV/Vis spectrophotometer as described in Section 2.2.1.

2.4. Effect of pH on Ketamine HCl Solubility

The solubility of ketamine HCl was assessed in different pH mediums to explore the optimal conditions for ketamine HCl solubilization. A total of 0.1 M of CB and PBS were used as solvents. Ketamine HCl was ground and added in excess to a glass vial (500 mg/mL) of various pH mediums including CB at pH 3.5 and 5.5, and PBS at pH 7.5 and 9.5. Further, vials were shaken at 240 rpm at 25 °C for 14 h. After, the vial content was centrifuged for 10 min at 6000× g, the obtained supernatant was separated, and the absorbance of each sample was analyzed using a UV/Vis spectrophotometer, as described in Section 2.2.1.

2.5. Effect of Surfactants on Ketamine HCl Solubility

After establishing the optimal pH mediums for ketamine solubilization, the effect of incorporating surfactants on ketamine HCl solubility was assessed. In brief, ketamine HCl was added in excess (500 mg/mL) to various pH mediums including CB at pH 3.5 and 5.5, containing different types of surfactants (e.g., SDS, PEG 400, PVP, Tween 80, LS, and PLX 188). The vial contents were shaken for 14 h at a speed of 240 rpm at 25 °C, followed by sample analysis using a UV/Vis spectrophotometer, as described in Section 2.2.1.

2.6. Statistical Analysis

The presented data are expressed as the average of the mean ± SD of three independent replicates (n = 3). The statistical significance of the presented data were analyzed using a one-way ANOVA and Dunnett’s test, as required, using GraphPad Prism 10 software (ns: not significant; * p < 0.05, ** p < 0.01; *** p < 0.001, **** p < 0.0001 indicate statistical significance).

3. Results and Discussion

3.1. Method Development for Ketamine Analysis

The absorption spectra of ketamine HCl in aqueous solution is shown in Figure 2A. The λmax was found to be 269 nm. Because the λmax was found to be similar in all evaluated mediums (water, CB pH 3.5, CB pH 5.5, PBS pH 7.5, and PBS pH 9.5) and was not affected by the pH of the dissolution medium, the same wavelength (269 nm) was used for all further measurements of ketamine HCl concentration. A calibration curve was constructed in the range of seven concentrations (25–500 µg/mL), as shown in Figure 2B. As illustrated in Table 1, the regression equation was y = 0.0019x + 0.0403, with an R2 of 0.9995. The LOD refers to the lowest concentration of an analyte that can be reliably detected but not necessarily quantified, while LOQ refers to the lowest concentration of an analyte that can be quantitatively measured with acceptable precision and accuracy, and they were found to be 3.39 and 10.27 µg/mL, respectively. Table 2 illustrates the results obtained for repeatability (intra-day) and intermediate precision (inter-day). In the case of the intra-day analysis, the RSD% results ranged from 1.21% to 4.43%, while the RE% ranged from 2.07 to 2.64%. In the case of the inter-day analysis, the RSD% ranged from 0.52 to 4.32%, while the RE% ranged from 0.56 to 1.08%.
The stability profile of ketamine HCl was assessed under different storage conditions to verify if any spontaneous degradation occurs after the samples are prepared. The results were expressed as the mean ± SD. The obtained data illustrated that the sample solutions were stable for up to 1 week when stored at 4 °C and 25 °C, with a degradation of less than 3% (Table 3). The stability of ketamine HCl when stored at 28 °C in a polypropylene syringe for 48 hours was also reported to be retained for over 95% of its initial concentrations [38]. In addition, the pH measurements remained stable throughout the study, with no signs of physical instability being observed, and thus, ketamine HCl appears to be a stable drug. It is important to note that this method is not intended to serve as a stability-indicating method for monitoring degradation products. Nonetheless, our initial stability testing demonstrated that UV-Vis spectroscopy is adequate for analyzing ketamine HCl. For future long-term stability evaluations, we plan to complement our UV-Vis method with an HPLC-based approach to enhance sensitivity and reliability.
Interference of the solvent or surfactants employed in the solubilization of drugs could lead to inaccurate measurements of the drug’s concentration [39]. In this regard, the interference in the different solvents (water, CB pH 3.5, CB pH 5.5, and PBS pH 7.5) that could be employed during the solubilization of ketamine HCl for IN delivery were evaluated. Interference was assessed by considering whether significant differences were observed at λmax (269 nm). As shown in Figure 3A, no peak was observed in any of the ketamine HCl-free solvents around 269 nm, while the results demonstrate well-defined peaks at the absorbance wavelength of 269 nm in the presence of ketamine HCl (Figure 3B). Moreover, surfactants typically absorb in the ultraviolet region of the spectrum, and thus, could alter the drug quantification using UV-Vis spectrophotometry [40,41]. Therfore, the interference of four surfactants (1% SDS, 1%PLX 407, 1%PLX 188, and 1%PEG 400) was also assessed, and clearly, no interference in the absence of ketamine HCl at λmax (269 nm) was observed (Figure 3C) in comparison to the well-defined peaks at the absorbance wavelength 269 nm, in the presence of ketamine HCl (Figure 3D). The absence of interference stems from the presence of an aromatic moiety in keamine that is absent in all evaluated surfactants in this study, resulting in a defined peak for examination at 269 nm. Similarly, Rapalli et al. also reported that no interference between the employed surfactants and buffers of the release media in the quantification of curcumin was observed [42].

3.2. Effect of Different Solvents on Ketamine HCl Solubility

Organic co-solvents were reported to play an important role in the solubilization of IN drugs. For instance, Nayzilam®, an example of a midazolam nasal spray that was developed by Proximagen, Ltd. (London, UK) and approved by the Food and Drug Administration (FDA) in 2019, was solubilized using different organic co-solvents, including ethanol and PG [19,43]. ValtocoTM is another formulation of IN diazepam reaching the market in 2020 that was solubilized by adding high amounts of organic cosolvents [43].
To identify the possible co-solvent that could be added to water to enhance the solubility of ketamine HCl, we first conducted a study to evaluate the solubility of ketamine HCl in various commonly used organic solvents (methanol, ethanol, PG, DMSO, and NMP) using UV–vis absorption spectrometry with independent calibration curves using the tested solvents. Figure 4 illustrates clearly that the solubility of ketamine was the highest in methanol (269.9 ± 25.4 mg/mL), followed by water (158.5 ± 10.2 mg/mL). The solubility of ketamine in methanol could be explained by many factors, including ketamine’s tendency to form hydrogen bonds with methanol utilizing its ketone functional group (-C=O) and an amine functional group (-NH2). Both functional groups could potentially be involved in hydrogen bonding with methanol [44,45,46]. However, the solubility of ketamine HCl in ethanol was more than ten times lower than in methanol, despite ethanol’s similar ability to form hydrogen bonds with ketamine HCl. Figure 4 clearly indicates that the solubility of ketamine HCl in organic solvents is related to solvent polarity. Methanol, with a relative polarity to water of 0.762, exhibits superior solubilization compared to ethanol, which has a relative polarity value of 0.654. It is worth mentioning that methanol was the only organic solvent that exhibited a better solubilization capability compared to water. Unfortunately, the use of methanol as a co-solvent for IN delivery is uncommon and might induce acute toxicity and irritation, and thus, it served only as an experimental tool in the early stages and was excluded from further consideration. Collectively, no common solvent was found to be suitable for significantly boosting the solubility of ketamine HCl in water. Therefore, a completely aqueous system was considered for further investigations.

3.3. Effect of pH on Ketamine HCl Solubility

The solution pH could induce a significant impact on the drug solubility profile, which in turn affects its absorption, biodistribution, and bioavailability in the site of action [47,48]. The nasal mucosa’s pH is in the range of 5.5 to 6.5 [49]. However, nasal formulation pH could exhibit a wider range (3.5–7.5) to consider other factors such as solubilization and stability of therapeutics. In this regard, a wide pH range at 3.5, 5.5, 7.5, and 9.5 was investigated, which is a standard approach in solubility evaluations. To further ensure that the choice of buffer type does not induce any alterations in ketamine solubility, two different buffer systems, including CB and PBS, were tested. This approach was implemented to confirm that the buffers would not interfere with the solubility of ketamine under experimental conditions. Overall, the buffer type did not significantly affect ketamine’s solubility (Figure 5), and a similar solubility profile was obtained in both CB and PBS across all tested pH values. The findings in Figure 5 also illustrate that pH is the primary influencing factor, where the highest solubilization profile of ketamine HCl was observed in acidic environments at pH 3.5 (222.8 ± 5.3 mg/mL at CB and 218.6 ± 5.2 mg/mL at PBS) and this is consistent with ketamine being a basic drug, followed by pH 5.5 (191.9 ± 13.3 mg/mL at CB and 179.4 ± 13.5 mg/mL at PBS). In contrast, ketamine HCl was poorly soluble in basic environments at pH 7.5 (76.7 ± 13.5 mg/mL at CB and 69.0 ± 5.0 mg/mL at PBS) and at pH 9.5 (69.8 ± 10.1 mg/mL at CB and 67.1 ± 5.2 mg/mL at PBS). This could be explained by the fact that ketamine is a weak base, and it possesses a pKa of 7.5, and thus, the protonation of amine (ionization) is promoted at a more acidic pH. However, when pH = pKa, ketamine HCl tends to become 50% protonated and 50% deprotonated, and thus, its solubility decreases, which has been observed at pH 7.5 (Figure 5). While at pH > pKa, the drug will become more deprotonated, and thus, its solubility decreases in the media. In this context, changes in the ionization state of drugs could significantly alter its solubility and PK profiles in different physiological environments. These findings are consistent with the fact that the pH of commercially available ketamine solutions for intravenous injections is maintained at an acidic level (around pH 3.5–5.5) to ensure the maximum stability and solubility of the drug. A systematic evaluation of the effects of buffer composition (type and ionic strength) on solubility was not conducted in this study, but this could be the focus of future studies.

3.4. Effect of Surfactants on Ketamine HCl Solubility

Surfactants play an important role in solubilizing the poorly soluble drugs, improving their dissolution profile and drug delivery, as well as enhancing their stability profile [26]. The idea behind employing surfactant strategy for improving the solubility of drugs emerged from a reported patent involving the incorporation of surfactants with ketamine in order to reduce the interfacial tension, and thus to reduce the tendency of ketamine HCl to precipitate [50]. To explore their impact on the solubility profile of ketamine HCl, different commonly used pharmaceutical surfactants were investigated under acidic pH environments including SDS, PEG 400, PVP, Tween 80, poloxamer 188, and lecithin Soya (Figure 6). Among the tested surfactants, 1% SDS was the potential surfactant for ketamine HCl solubilization (Figure 7). Under CB at pH 3.5 environment, the solubility of ketamine HCl improved from 222.8 ± 5.3 mg/mL to 256.1 ± 15.4 mg/mL (16% enhancement) in the presence of 1% SDS (Figure 7). Similarly, SDS was previously reported to significantly improve the solubility of various drugs [51,52]. Surprisingly, the solubility of ketamine HCl decreased with the incorporation of 1% PEG 400 and further decreased with 10% PEG 400, as shown in Figure 7. This can be explained by the salting-out effect, where PEG, a hydrophilic polymer, undergoes high solvation in water, reducing water’s capacity to dissolve other molecules, including ketamine HCl. A similar pattern was observed with PVP as a surfactant; the solubility of ketamine HCl decreased more with 20% PVP compared to 10% PVP. This behavior for both PEG and PVP is due to their high solvation in water, leading to the reduced solvation of ketamine HCl. Conversely, the addition of 10% Tween 80 slightly enhanced the solubility of ketamine HCl by approximately 5%, and the addition of 20% Tween 80 enhanced the solubility by around 9%. Unlike PEG 400 and PVP, Tween 80 can form micelles above its critical micelle concentration. This results in a lower salting-out effect and provides a greater solubilization capacity within the hydrophobic compartments of the formed micelles. LS and PLX 188 are two micelle-forming surfactants, and they slightly improved the solubility of ketamine to a lower degree compared to Tween or SDS. Collectively, our results indicate that SDS at 1% w/v is the optimal surfactant for improving the solubility of ketamine HCl, despite only providing marginal enhancement in solubilization.

4. Conclusions

This study explored the solubility profile of ketamine HCl for intranasal delivery by manipulating variables such as co-solvent effects, surfactant incorporation, and pH adjustments. The findings revealed a marked improvement in ketamine HCl solubility, particularly through pH optimization and the addition of surfactants like SDS. A preliminary one-week stability assessment showed consistent solubility and pH stability, supporting the preparation of highly concentrated ketamine HCl solutions suitable for IN delivery, which is critical given the limited dose volume per nostril and the high therapeutic doses required.
These outcomes highlight the potential of these solubilization strategies to address the solubility limitations of ketamine HCl, enabling the preparation of highly concentrated ketamine HCl formulations for intranasal delivery, which could improve both the accessibility and efficacy of ketamine-based therapies. Future studies should focus on longer-term stability testing to establish self-life and formulation robustness under various storage conditions. Additionally, applying these approaches to other active pharmaceutical ingredients may broaden intranasal delivery applications, enhancing bioavailability and therapeutic efficacy in clinical settings.

Author Contributions

S.I.: Data curation, Formal analysis, Writing—original draft. A.S.: Data curation, Formal analysis. M.A.: Data curation, Formal analysis, Writing—review and editing. L.A.: Supervision, Writing—review and editing. K.A.: Supervision, Writing—review and editing. O.R.: Supervision, Writing—review and editing. A.M.A.: Conceptualization, Main supervision, Validation, Funding acquisition, Methodology, Project administration, Resources, Writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

Dr. Alkilany’s laboratory is supported by funding from Qatar University and the Qatar Research, Development, and Innovation (QRDI) Council. Open Access funding provided by Qatar University.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

The data supporting this article have been included in this paper.

Acknowledgments

The authors acknowledge the financial support and Open Access funding from Qatar University.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Peltoniemi, M.A.; Hagelberg, N.M.; Olkkola, K.T.; Saari, T.I. Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy. Clin. Pharmacokinet. 2016, 55, 1059–1077. [Google Scholar] [CrossRef] [PubMed]
  2. Mion, G.; Villevieille, T. Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings). CNS Neurosci. Ther. 2013, 19, 370–380. [Google Scholar] [CrossRef] [PubMed]
  3. Li, L.; Vlisides, P.E. Ketamine: 50 Years of Modulating the Mind. Front. Hum. Neurosci. 2016, 10, 612. [Google Scholar] [CrossRef] [PubMed]
  4. Das, J. Repurposing of Drugs-The Ketamine Story. J. Med. Chem. 2020, 63, 13514–13525. [Google Scholar] [CrossRef]
  5. Jelen, L.A.; Young, A.H.; Stone, J.M. Ketamine: A tale of two enantiomers. J. Psychopharmacol. 2021, 35, 109. [Google Scholar] [CrossRef]
  6. Nikolin, S.; Rodgers, A.; Schwaab, A.; Bahji, A.; Zarate, C.; Vazquez, G.; Loo, C. Ketamine for the treatment of major depression: A systematic review and meta-analysis. eClinicalMedicine 2023, 62, 102127. [Google Scholar] [CrossRef]
  7. Bahji, A.; Vazquez, G.H.; Zarate, C.A., Jr. Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. J. Affect. Disord. 2021, 278, 542–555. [Google Scholar] [CrossRef]
  8. Trimmel, H.; Helbok, R.; Staudinger, T.; Jaksch, W.; Messerer, B.; Schöchl, H.; Likar, R. S(+)-ketamine: Current trends in emergency and intensive care medicine. Wien. Klin. Wochenschr. 2018, 130, 356. [Google Scholar] [CrossRef]
  9. McIntyre, R.S.; Rosenblat, J.D.; Nemeroff, C.B.; Sanacora, G.; Murrough, J.W.; Berk, M.; Brietzke, E.; Dodd, S.; Gorwood, P.; Ho, R.; et al. Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation. Am. J. Psychiatry 2021, 178, 383–399. [Google Scholar] [CrossRef]
  10. Nikayin, S.; Murphy, E.; Krystal, J.H.; Wilkinson, S.T. Long-term safety of ketamine and esketamine in treatment of depression. Expert Opin. Drug Saf. 2022, 21, 777–787. [Google Scholar] [CrossRef]
  11. Bali, A.; Dang, A.K.; Gonzalez, D.A.; Kumar, R.; Asif, S. Clinical Uses of Ketamine in Children: A Narrative Review. Cureus 2022, 14, e27065. [Google Scholar] [CrossRef] [PubMed]
  12. Riccardi, A.; Guarino, M.; Serra, S.; Spampinato, M.D.; Vanni, S.; Shiffer, D.; Voza, A.; Fabbri, A.; De Iaco, F. Narrative Review: Low-Dose Ketamine for Pain Management. J. Clin. Med. 2023, 12, 3256. [Google Scholar] [CrossRef] [PubMed]
  13. Nowacka, A.; Borczyk, M. Ketamine applications beyond anesthesia—A literature review. Eur. J. Pharmacol. 2019, 860, 172547. [Google Scholar] [CrossRef]
  14. Zanos, P.; Moaddel, R.; Morris, P.J.; Riggs, L.M.; Highland, J.N.; Georgiou, P.; Pereira, E.F.R.; Albuquerque, E.X.; Thomas, C.J.; Zarate, C.A.; et al. Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms. Pharmacol. Rev. 2018, 70, 621–660. [Google Scholar] [CrossRef] [PubMed]
  15. Jeong, S.H.; Jang, J.H.; Lee, Y.B. Drug delivery to the brain via the nasal route of administration: Exploration of key targets and major consideration factors. J. Pharm. Investig. 2022, 53, 119–152. [Google Scholar] [CrossRef] [PubMed]
  16. Keller, L.A.; Merkel, O.; Popp, A. Intranasal drug delivery: Opportunities and toxicologic challenges during drug development. Drug Deliv. Transl. Res. 2021, 12, 735–757. [Google Scholar] [CrossRef]
  17. Laffleur, F.; Keckeis, V. Advances in drug delivery systems: Work in progress still needed? Int. J. Pharm. 2020, 590, 119912. [Google Scholar] [CrossRef]
  18. Andrade, C. Ketamine for Depression, 4: In What Dose, at What Rate, by What Route, for How Long, and at What Frequency? J. Clin. Psychiatry 2017, 78, 10106. [Google Scholar] [CrossRef]
  19. Pires, P.C.; Rodrigues, M.; Alves, G.; Santos, A.O. Strategies to Improve Drug Strength in Nasal Preparations for Brain Delivery of Low Aqueous Solubility Drugs. Pharmaceutics 2022, 14, 588. [Google Scholar] [CrossRef]
  20. Chung, S.; Peters, J.M.; Detyniecki, K.; Tatum, W.; Rabinowicz, A.L.; Carrazana, E. The nose has it: Opportunities and challenges for intranasal drug administration for neurologic conditions including seizure clusters. Epilepsy Behav. Rep. 2023, 21, 100581. [Google Scholar] [CrossRef]
  21. Wolfe, T.R.; Braude, D.A. Intranasal Medication Delivery for Children: A Brief Review and Update. Pediatrics 2010, 126, 532–537. [Google Scholar] [CrossRef] [PubMed]
  22. Del Pizzo, J.; Callahan, J.M. Intranasal medications in pediatric emergency medicine. Pediatr. Emerg. Care 2014, 30, 496–501. [Google Scholar] [CrossRef] [PubMed]
  23. Abrams, R.; Morrison, J.E.; Villasenor, A.; Hencmann, D.; Da Fonseca, M.; Mueller, W. Safety and effectiveness of intranasal administration of sedative medications (ketamine, midazolam, or sufentanil) for urgent brief pediatric dental procedures. Anesth. Prog. 1993, 40, 63. [Google Scholar] [PubMed]
  24. Tsze, D.S.; Steele, D.W.; MacHan, J.T.; Akhlaghi, F.; Linakis, J.G. Intranasal ketamine for procedural sedation in pediatric laceration repair: A preliminary report. Pediatr. Emerg. Care 2012, 28, 767–770. [Google Scholar] [CrossRef]
  25. Saboo, S.; Bapat, P.; Moseson, D.E.; Kestur, U.S.; Taylor, L.S. Exploring the role of surfactants in enhancing drug release from amorphous solid dispersions at higher drug loadings. Pharmaceutics 2021, 13, 735. [Google Scholar] [CrossRef]
  26. Pokhrel, D.R.; Sah, M.K.; Gautam, B.; Basak, H.K.; Bhattarai, A.; Chatterjee, A. A recent overview of surfactant-drug interactions and their importance. RSC Adv. 2023, 13, 17685–17704. [Google Scholar] [CrossRef]
  27. Liao, Y.; Li, Z.; Zhou, Q.; Sheng, M.; Qu, Q.; Shi, Y.; Yang, J.; Lv, L.; Dai, X.; Shi, X. Saponin surfactants used in drug delivery systems: A new application for natural medicine components. Int. J. Pharm. 2021, 603, 120709. [Google Scholar] [CrossRef]
  28. Tahan, A.; Khojandi, M.; Salari, A.A. The theoretical investigation of solvent effects on the relative stability and 15N NMR shielding of antidepressant heterocyclic drug. Russ. J. Phys. Chem. A 2016, 90, 130–135. [Google Scholar] [CrossRef]
  29. Zheng, M.; Chen, J.; Chen, G.; Farajtabar, A.; Zhao, H. Solubility modelling and solvent effect for domperidone in twelve green solvents. J. Mol. Liq. 2018, 261, 50–56. [Google Scholar] [CrossRef]
  30. Lomba, L.; García, C.B.; Ribate, M.P.; Giner, B.; Zuriaga, E. Applications of Deep Eutectic Solvents Related to Health, Synthesis, and Extraction of Natural Based Chemicals. Appl. Sci. 2021, 11, 10156. [Google Scholar] [CrossRef]
  31. Almotairy, A.; Almutairi, M.; Althobaiti, A.; Alyahya, M.; Sarabu, S.; Alzahrani, A.; Zhang, F.; Bandari, S.; Repka, M.A. Effect of pH Modifiers on the Solubility, Dissolution Rate, and Stability of Telmisartan Solid Dispersions Produced by Hot-melt Extrusion Technology. J. Drug Deliv. Sci. Technol. 2021, 65, 102674. [Google Scholar] [CrossRef] [PubMed]
  32. Gaohua, L.; Miao, X.; Dou, L. Crosstalk of physiological pH and chemical pKa under the umbrella of physiologically based pharmacokinetic modeling of drug absorption, distribution, metabolism, excretion, and toxicity. Expert Opin. Drug Metab. Toxicol. 2021, 17, 1103–1124. [Google Scholar] [CrossRef] [PubMed]
  33. Al Ktash, M.; Stefanakis, M.; Boldrini, B.; Ostertag, E.; Brecht, M. Characterization of Pharmaceutical Tablets Using UV Hyperspectral Imaging as a Rapid In-Line Analysis Tool. Sensors 2021, 21, 4436. [Google Scholar] [CrossRef] [PubMed]
  34. Brands, R.; Tebart, N.; Thommes, M.; Bartsch, J. UV/Vis spectroscopy as an in-line monitoring tool for tablet content uniformity. J. Pharm. Biomed. Anal. 2023, 236, 115721. [Google Scholar] [CrossRef] [PubMed]
  35. Di Bartolomeo, A.; Gavat, C.-C. Ultraviolet (UV) Spectrophotometric Analysis of Ketoprofen in Tablets–Statistical Validation of Proposed Method. Mater. Proc. 2023, 14, 60. [Google Scholar] [CrossRef]
  36. Rambla-Alegre, M.; Esteve-Romero, J.; Carda-Broch, S. Is it really necessary to validate an analytical method or not? That is the question|Enhanced Reader. J. Chromatogr. A 2012, 1232, 101–109. [Google Scholar] [CrossRef]
  37. Peris-Vicente, J.; Esteve-Romero, J.; Carda-Broch, S. Validation of Analytical Methods Based on Chromatographic Techniques: An Overview. Anal. Sep. Sci. 2015, 5, 1757–1808. [Google Scholar] [CrossRef]
  38. Beiler, B.; Barraud, D.; Vigneron, J.; Demoré, B. Physicochemical stability of an admixture of lidocaine and ketamine in polypropylene syringe used in opioid-free anaesthesia. Eur. J. Hosp. Pharm. 2020, 27, e79–e83. [Google Scholar] [CrossRef]
  39. Espinoza, S.M.; Guadalupe, R.; Pimentel, C.; San, E.; Martinez, M.; Casa~ Nas Pimentel, R.G. UV–Vis spectroscopic quantification of residual acetone during the development of nanoparticulate drug delivery systems. Pharm. Dev. Technol. 2019, 24, 751–760. [Google Scholar] [CrossRef]
  40. Saraf, A.; Sharma, S.; Sachar, S. Evaluation of surfactants as solubilizing medium for levofloxacin. J. Mol. Liq. 2020, 319, 114060. [Google Scholar] [CrossRef]
  41. Kamberi, M.; Tran, T.N. UV–visible spectroscopy as an alternative to liquid chromatography for determination of everolimus in surfactant-containing dissolution media: A useful approach based on solid-phase extraction. J. Pharm. Biomed. Anal. 2012, 70, 94–100. [Google Scholar] [CrossRef] [PubMed]
  42. Rapalli, V.K.; Kaul, V.; Gorantla, S.; Waghule, T.; Dubey, S.K.; Pandey, M.M.; Singhvi, G. UV Spectrophotometric method for characterization of curcumin loaded nanostructured lipid nanocarriers in simulated conditions: Method development, in-vitro and ex-vivo applications in topical delivery. Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 2020, 224, 117392. [Google Scholar] [CrossRef] [PubMed]
  43. Boddu, S.H.S.; Kumari, S. A Short Review on the Intranasal Delivery of Diazepam for Treating Acute Repetitive Seizures. Pharmaceutics 2020, 12, 1167. [Google Scholar] [CrossRef] [PubMed]
  44. Duereh, A.; Guo, H.; Honma, T.; Hiraga, Y.; Sato, Y.; Lee Smith, R.; Inomata, H. Solvent Polarity of Cyclic Ketone (Cyclopentanone, Cyclohexanone): Alcohol (Methanol, Ethanol) Renewable Mixed-Solvent Systems for Applications in Pharmaceutical and Chemical Processing. Ind. Eng. Chem. Res. 2018, 57, 7331–7344. [Google Scholar] [CrossRef]
  45. Hoerr, C.W.; Harwood, H.J.; Ralston, A.W. Solubilities of high molecular weight symmetrical normal aliphatic secondary amines. J. Org. Chem. 1944, 9, 201–210. [Google Scholar] [CrossRef]
  46. Spencer, J.N.; Wolbach, W.S.; Hovick, J.W.; Ansel, L.; Modarress, K.J. Hydrogen bonding by alcohols and amines. J. Solution Chem. 1985, 14, 805–814. [Google Scholar] [CrossRef]
  47. Abuhelwa, A.Y.; Williams, D.B.; Upton, R.N.; Foster, D.J.R. Food, gastrointestinal pH, and models of oral drug absorption. Eur. J. Pharm. Biopharm. 2017, 112, 234–248. [Google Scholar] [CrossRef]
  48. Shoghi, E.; Fuguet, E.; Bosch, E.; Ràfols, C. Solubility–pH profiles of some acidic, basic and amphoteric drugs. Eur. J. Pharm. Sci. 2013, 48, 291–300. [Google Scholar] [CrossRef]
  49. Henriques, P.; Fortuna, A.; Doktorovová, S. Spray dried powders for nasal delivery: Process and formulation considerations. Eur. J. Pharm. Biopharm. 2022, 176, 1–20. [Google Scholar] [CrossRef]
  50. Gebhardt, U.; Knoch, A.; Rauchfuss, R.; Schneider, M. Stable Ketamine Solutions. Patent WO1994023711A1, 27 October 1994. [Google Scholar]
  51. Huang, Z.; Parikh, S.; Fish, W.P. Interactions between a poorly soluble cationic drug and sodium dodecyl sulfate in dissolution medium and their impact on in vitro dissolution behavior. Int. J. Pharm. 2018, 535, 350–359. [Google Scholar] [CrossRef]
  52. Mai, N.N.S.; Otsuka, Y.; Kawano, Y.; Hanawa, T. Preparation and characterization of solid dispersions composed of curcumin, hydroxypropyl cellulose and/or sodium dodecyl sulfate by grinding with vibrational ball milling. Pharmaceuticals 2020, 13, 383. [Google Scholar] [CrossRef] [PubMed]
Pharmaceutics 16 01502 g001
Figure 1. Chemical structure of ketamine enantiomers. Both stereoisomers, (S)-ketamine and (R)-ketamine, are non-superimposable mirror images. Figure created in ChemDraw.
Figure 1. Chemical structure of ketamine enantiomers. Both stereoisomers, (S)-ketamine and (R)-ketamine, are non-superimposable mirror images. Figure created in ChemDraw.
Pharmaceutics 16 01502 g001
Pharmaceutics 16 01502 g002
Figure 2. (A) UV–Vis absorption spectrum of ketamine HCl (200 µg/mL) in 0.1 M CB, pH = 3.5 between 200 and 400 nm with λmax at 269 nm. (B) Calibration curve of ketamine HCl in 0.1 M CB, pH = 3.5 at 269 nm.
Figure 2. (A) UV–Vis absorption spectrum of ketamine HCl (200 µg/mL) in 0.1 M CB, pH = 3.5 between 200 and 400 nm with λmax at 269 nm. (B) Calibration curve of ketamine HCl in 0.1 M CB, pH = 3.5 at 269 nm.
Pharmaceutics 16 01502 g002
Pharmaceutics 16 01502 g003
Figure 3. UV–Vis absorption spectrum of ketamine HCl (200 µg/mL) in different solvents without (A) and with ketamine HCl (B), and in solutions of various surfactants without (C) and with ketamine HCl (D) in the range of 200–400 nm. Data are expressed as mean ± SD (n = 3).
Figure 3. UV–Vis absorption spectrum of ketamine HCl (200 µg/mL) in different solvents without (A) and with ketamine HCl (B), and in solutions of various surfactants without (C) and with ketamine HCl (D) in the range of 200–400 nm. Data are expressed as mean ± SD (n = 3).
Pharmaceutics 16 01502 g003
Pharmaceutics 16 01502 g004
Figure 4. Solubility of ketamine HCl in different co-solvents. Data are expressed as mean ± SD (n = 3). Statistical significance was calculated using 1-way ANOVA and Dunnett’s test (**** p < 0.0001 indicate statistical significance compared to water).
Figure 4. Solubility of ketamine HCl in different co-solvents. Data are expressed as mean ± SD (n = 3). Statistical significance was calculated using 1-way ANOVA and Dunnett’s test (**** p < 0.0001 indicate statistical significance compared to water).
Pharmaceutics 16 01502 g004
Pharmaceutics 16 01502 g005
Figure 5. Solubility of ketamine HCl as a function of pH in (A) 0.1 M CB and (B) 0.1 M PBS. Data are expressed as mean ± SD (n = 3). Statistical significance was calculated using 1-way ANOVA and Dunnett’s test (** p < 0.01, and **** p < 0.0001 indicate statistical significance compared to the pH 3.5 condition).
Figure 5. Solubility of ketamine HCl as a function of pH in (A) 0.1 M CB and (B) 0.1 M PBS. Data are expressed as mean ± SD (n = 3). Statistical significance was calculated using 1-way ANOVA and Dunnett’s test (** p < 0.01, and **** p < 0.0001 indicate statistical significance compared to the pH 3.5 condition).
Pharmaceutics 16 01502 g005
Pharmaceutics 16 01502 g006
Figure 6. Chemical structures of the used surfactants for ketamine HCl solubilization. Figure was created in ChemDraw.
Figure 6. Chemical structures of the used surfactants for ketamine HCl solubilization. Figure was created in ChemDraw.
Pharmaceutics 16 01502 g006
Pharmaceutics 16 01502 g007
Figure 7. Solubility of ketamine HCl with different surfactants in CB with pH 3.5 (control) with different surfactants. Data are expressed as mean ± SD (n = 3). Statistical significance calculated using 1-way ANOVA and Dunnett’s test (ns = not significant, * p < 0.05 indicate statistical significance compared to the control).
Figure 7. Solubility of ketamine HCl with different surfactants in CB with pH 3.5 (control) with different surfactants. Data are expressed as mean ± SD (n = 3). Statistical significance calculated using 1-way ANOVA and Dunnett’s test (ns = not significant, * p < 0.05 indicate statistical significance compared to the control).
Pharmaceutics 16 01502 g007
Table 1. Results of regression analysis of data for the quantitation of ketamine HCl.
Table 1. Results of regression analysis of data for the quantitation of ketamine HCl.
Linear range (µg/mL) 25–500
Regression equation Y = 0.0019x + 0.0403
Standard error of slope 1.9 × 10−5
Standard error of intercept 1.96 × 10−3
R2 (mean ± SD) 0.9995 ± 0.0074
LOD (µg/mL) 3.39
LOQ (µg/mL) 10.27
Table 2. Precision (%, RSD) and accuracy (%, RE) for propofol, ketamine HCl. Data are expressed as mean ± SD (n = 12).
Table 2. Precision (%, RSD) and accuracy (%, RE) for propofol, ketamine HCl. Data are expressed as mean ± SD (n = 12).
Added Concentration
(µg/mL)		Intra-Day (n = 12)Inter-Day (n = 12)
Concentration Found
(Mean ± SD)		Precision
(RSD, %)		Accuracy
(RE, %)		Concentration Found
(Mean ± SD)		Precision
(RSD, %)		Accuracy
(RE, %)
2525.51 ± 1.134.432.0725.16 ± 1.084.320.66
100102.35 ± 2.362.312.35100.56 ± 1.831.820.56
250256.61 ± 3.121.212.64252.71 ± 1.330.521.08
Table 3. Stability results of ketamine HCl at room temperature (25 °C) and in the refrigerator (4 °C). Data are expressed as mean ± SD (n = 6).
Table 3. Stability results of ketamine HCl at room temperature (25 °C) and in the refrigerator (4 °C). Data are expressed as mean ± SD (n = 6).
Concentration (µg/mL)
(Mean ± SD)
25100250
Room temperature
(25 °C)		Day 124.26 ± 3.71100.64 ± 0.92255.91 ± 0.30
Day 224.46 ± 1.4899.77 ± 0.97253.10 ± 5.26
1 week25.82 ± 0.90103.89 ± 0.28250.12 ± 0.30
Refrigerator
(4 °C)		Day 124.15 ± 1.15100.29 ± 0.79255.38 ± 3.65
Day 225.12 ± 0.9097.00 ± 1.26254.42 ± 3.58
1 week25.21 ± 1.33100.82 ± 2.57254.50 ± 3.30
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Idoudi, S.; Saleh, A.; Akkbik, M.; Amine, L.; Alansari, K.; Rachid, O.; Alkilany, A.M. Investigating Strategies to Enhance the Aqueous Solubility of Ketamine HCl for Intranasal Delivery. Pharmaceutics 2024, 16, 1502. https://doi.org/10.3390/pharmaceutics16121502

AMA Style

Idoudi S, Saleh A, Akkbik M, Amine L, Alansari K, Rachid O, Alkilany AM. Investigating Strategies to Enhance the Aqueous Solubility of Ketamine HCl for Intranasal Delivery. Pharmaceutics. 2024; 16(12):1502. https://doi.org/10.3390/pharmaceutics16121502

Chicago/Turabian Style

Idoudi, Sourour, Alaaeldin Saleh, Mohammed Akkbik, Leena Amine, Khalid Alansari, Ousama Rachid, and Alaaldin M. Alkilany. 2024. "Investigating Strategies to Enhance the Aqueous Solubility of Ketamine HCl for Intranasal Delivery" Pharmaceutics 16, no. 12: 1502. https://doi.org/10.3390/pharmaceutics16121502

APA Style

Idoudi, S., Saleh, A., Akkbik, M., Amine, L., Alansari, K., Rachid, O., & Alkilany, A. M. (2024). Investigating Strategies to Enhance the Aqueous Solubility of Ketamine HCl for Intranasal Delivery. Pharmaceutics, 16(12), 1502. https://doi.org/10.3390/pharmaceutics16121502

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Article metric data becomes available approximately 24 hours after publication online.
Back to TopTop