Formulation, Physicochemical Characterization, and In-Vitro Dissolution Enhancement of Ibrutinib Nanosuspension Prepared by the Nanoprecipitation Technique

Oral administration remains the most widely used and preferred route of drug delivery on account of its convenience, ease of administration, high patient compliance and cost-effective manufacturing. However, the clinical usefulness of a large proportion of orally administered drugs is limited not by their intrinsic pharmacological activity but by inadequate aqueous solubility and consequent poor dissolution in gastrointestinal fluids. By some estimates, more than 40% of new chemical entities emerging from contemporary drug-discovery programmes are poorly water-soluble, and this proportion is expected to rise further as high-throughput screening continues to identify potent but lipophilic candidates. The Biopharmaceutics Classification System (BCS) categorises such drugs on the basis of their aqueous solubility and intestinal permeability; BCS Class II drugs, which combine low solubility with high permeability, are of particular formulation interest because their oral bioavailability is generally dissolution-rate limited rather than permeability-limited. For this class of drugs, any formulation strategy capable of increasing the effective dissolution rate can be expected to translate into a meaningful improvement in oral absorption.

Ibrutinib is a potent, orally active, first-in-class inhibitor of Bruton's tyrosine kinase (BTK), an enzyme central to B-cell receptor signalling. By forming an irreversible covalent bond with a cysteine residue (Cys481) in the BTK active site, Ibrutinib blocks downstream phosphorylation events and B-cell proliferation and survival pathways. It is used clinically in the treatment of mantle cell lymphoma, chronic lymphocytic leukaemia/small lymphocytic lymphoma (including cases with 17p deletion), Waldenström's macroglobulinemia, marginal zone lymphoma, and chronic graft-versus-host disease. Ibrutinib is a BCS Class II compound with a reported aqueous solubility of only 0.003 mg/mL and a molecular weight of 440.5 g/mol (C25H24N6O2); the drug is rapidly but incompletely absorbed after oral dosing (Cmax ≈ 35 ng/mL; tmax 1–2 h), and its extensive hepatic metabolism (CYP3A4/CYP2D6) together with poor aqueous solubility contributes to variable systemic exposure. Improving the dissolution characteristics of Ibrutinib is therefore a rational and clinically relevant formulation objective.

Figure 1. Chemical structure of Ibrutinib (C25H24N6O2; MW 440.5 g/mol)

According to the Noyes–Whitney equation, the dissolution rate of a solid drug is directly proportional to its available surface area and to the difference between its saturation solubility and the bulk concentration in the dissolution medium. Reduction of particle size into the nanometer range increases the specific surface area available for solvation and, in many cases, also increases the apparent saturation solubility, thereby enhancing dissolution velocity. Numerous strategies — including micronisation, solid dispersions, inclusion complexation with cyclodextrins, self-emulsifying systems, liposomes and lipid-based carriers — have been explored to overcome the dissolution-limited absorption of BCS Class II drugs, but each carries specific constraints related to drug loading, manufacturing complexity, excipient toxicity, or physical/chemical stability.

Nanosuspension technology has emerged as a comparatively simple and versatile alternative for poorly water-soluble drugs that are insoluble in both aqueous and organic media, a situation in which many classical solubilisation techniques are unworkable. A pharmaceutical nanosuspension is defined as a colloidal, biphasic dispersion of pure drug particles, typically 200–600 nm in mean diameter, stabilised in an aqueous (or other suitable) vehicle by surfactants or polymers, without the need to alter the crystalline form or chemical structure of the drug. Because the drug remains in its native crystalline or amorphous state at reduced particle size, nanosuspensions can achieve high drug loading, improved wetting, increased saturation solubility and a correspondingly higher dissolution rate, which together may translate into improved and more consistent oral bioavailability. Nanosuspensions can be prepared by "top-down" approaches such as media milling and high-pressure homogenisation, or by "bottom-up" approaches such as nanoprecipitation (solvent–antisolvent precipitation), in which a drug solution in a water-miscible organic solvent is introduced into an aqueous antisolvent phase containing a stabiliser, causing rapid nucleation and growth of nano sized drug particles as the organic solvent diffuses into the aqueous phase. Nanoprecipitation is attractive because it avoids the high energy input and equipment-related contamination risks associated with milling and homogenisation techniques.

Against this background, the present study was undertaken to formulate an Ibrutinib nanosuspension by the nanoprecipitation technique using three pharmaceutically established stabilising polymers — Carbopol, Ethyl Cellulose and Sodium Carboxymethyl Cellulose (Na CMC) — in combination with PVP K-30 and sodium lauryl sulfate, and to systematically evaluate the influence of stabiliser type and concentration on particle size, polydispersity, zeta potential, drug content, entrapment efficiency, saturation solubility and in-vitro dissolution behaviour. The overall goal was to identify an optimised Ibrutinib nanosuspension formulation with improved dissolution characteristics relative to the unmodified drug, as a step toward addressing the bioavailability limitations associated with its poor aqueous solubility.

2. MATERIALS AND METHODS

2.1 Materials

Ibrutinib was received as a gift sample from SURA LABS, Dilsukhnagar, Hyderabad, India. Carbopol, Ethyl Cellulose, Sodium Carboxymethyl Cellulose (Na CMC), PVP K-30, sodium lauryl sulfate (SLS) and methanol were procured from Merck Limited, Mumbai, India. Purified water was used throughout the study. All materials used are summarised in Table 1.

 

 

Figure 2. UV absorption spectrum of Ibrutinib in 0.1N HCl showing λmax at 288 nm

Table 7. Calibration data for Ibrutinib in 0.1N HCl at 288 nm

Concentration (µg/mL)	Absorbance
0	0.000
5	0.119
10	0.215
15	0.322
20	0.412
25	0.535

 

 

Figure 3. Calibration curve of Ibrutinib in 0.1N HCl (288 nm); y = 0.0209x + 0.0057, R² = 0.9984

 

 

Figure 4a. FTIR spectrum of pure Ibrutinib

 

 

Figure 4b. FTIR spectrum of the optimised (F3) Ibrutinib nanosuspension

 

 

Figure 5. DSC thermogram of pure Ibrutinib

Table 8. Percentage yield, drug content and entrapment efficiency of Ibrutinib nanosuspension formulations (F1–F9)

Formulation	Entrapment efficiency (%)	Drug content (%)	Percentage yield (%)
F1	92.51	86.10	90.33
F2	94.63	94.26	91.63
F3	98.90	99.63	94.25
F4	85.12	84.26	74.63
F5	90.20	91.56	78.33
F6	94.99	92.62	86.30
F7	83.25	78.23	76.99
F8	85.63	86.60	85.12
F9	96.39	90.22	88.48

 

 

Figure 6. Entrapment efficiency, drug content and percentage yield of formulations F1–F9

Table 9. Particle size, polydispersity index and zeta potential of Ibrutinib nanosuspension formulations (F1–F9)

Formulation	Particle size (nm)	PDI	Zeta potential (mV)
F1	278.6	0.75	−22.16
F2	312.4	0.56	−21.30
F3	341.8	0.43	−34.44
F4	365.2	1.10	−18.51
F5	398.7	0.71	−27.19
F6	453.2	0.60	−19.32
F7	329.5	0.52	−25.49
F8	295.8	1.20	−26.56
F9	260.4	1.31	−21.22

 

 

Figure 7. Mean particle size (bars) and polydispersity index (line) of formulations F1–F9

 

 

Figure 8. Representative zeta-potential distribution profile of the optimised (F3) Ibrutinib nanosuspension

Table 11. Cumulative percentage in-vitro drug release from Ibrutinib nanosuspension formulations (F1–F9) in 0.1N HCl

Time (min)	F1	F2	F3	F4	F5	F6	F7	F8	F9
0	0	0	0	0	0	0	0	0	0
5	22.10	30.10	54.12	20.15	34.15	45.93	18.43	23.14	27.41
10	26.51	38.08	70.66	32.25	49.36	56.20	26.96	30.94	33.75
15	42.36	50.92	74.25	40.76	53.02	62.09	33.09	48.37	51.14
20	45.95	56.36	80.36	48.91	56.20	70.34	42.14	55.19	58.43
25	53.02	62.14	87.44	57.24	70.14	76.66	58.27	62.24	65.18
30	56.96	67.61	92.03	63.86	75.66	80.25	63.19	68.83	71.27
45	61.02	79.20	97.12	67.34	78.93	85.11	79.34	70.14	75.54
60	73.95	89.66	98.98	72.63	84.75	88.39	80.15	85.72	83.78

 

 

Figure 9. Cumulative in-vitro drug release profiles of formulations F1–F9 in 0.1N HCl (0–60 min)

 

 

Figure 10. Scanning electron micrograph of the optimised (F3) Ibrutinib nanosuspension

Taking together particle size, PDI, zeta potential, drug content, entrapment efficiency, percentage yield, saturation solubility and in-vitro release performance, formulation F3 (Ibrutinib:Carbopol, 140:200 mg) was identified as the optimised Ibrutinib nanosuspension prepared by nanoprecipitation.

DISCUSSION

The present findings demonstrate that nanoprecipitation is a viable, low-energy technique for converting the poorly water-soluble BCS Class II drug Ibrutinib into a stable, sub-micron nanosuspension. The measured aqueous solubility of the pure drug (0.201–0.565 µg/mL depending on medium) confirms the severity of its dissolution-limited behaviour and supports the rationale, articulated in the Introduction, that particle-size reduction according to Noyes–Whitney principles should meaningfully increase the effective surface area and dissolution rate of the drug.

Comparison across the nine formulations shows that particle size alone is not a sufficient predictor of nanosuspension quality. Formulation F9 (Na CMC, 200 mg) produced the smallest mean particle size (260.4 nm), yet its PDI (1.31) and zeta potential (−21.22 mV) were both less favourable than those of F3, and its cumulative drug release (83.78% at 60 min) was correspondingly lower than that of F3. In contrast, F3, despite a somewhat larger mean particle size (341.8 nm), combined the narrowest size distribution (PDI 0.43), the highest-magnitude zeta potential (−34.44 mV) and the greatest cumulative release (98.98%) in the series. This pattern indicates that the uniformity of the particle population and the strength of the stabilising interfacial layer — rather than particle size in isolation — are the principal determinants of both physical stability and functional dissolution performance in this system, a conclusion broadly consistent with reports on nanosuspension formulation of other poorly soluble drugs, where a suitably charged and sterically stabilising polymer layer was similarly identified as critical to preventing Ostwald ripening and aggregation during and after precipitation.The concentration-dependent trend among the Carbopol-stabilised batches (F1 → F2 → F3, with increasing Carbopol from 100 to 200 mg) toward higher entrapment efficiency, drug content, yield, zeta potential and dissolution rate suggests that Carbopol, an anionic, high-molecular-weight polyacrylic acid polymer, provides progressively stronger electrosteric stabilisation of the precipitating drug nanoparticles as its concentration is increased, limiting particle growth and coalescence during the antisolvent precipitation step. This is consistent with earlier reports describing polymeric and amphiphilic stabilisers as effective agents for controlling nanocrystal growth and preventing agglomeration during nanoprecipitation and related bottom-up processes. By contrast, the Ethyl-Cellulose-stabilised formulations (F4–F6) showed comparatively larger particle sizes, lower zeta potential magnitudes, and slower dissolution, plausibly reflecting the more hydrophobic, film-forming nature of Ethyl Cellulose, which may retard both particle stabilisation during precipitation and subsequent wetting and dissolution of the drug in the aqueous medium. The Na-CMC-stabilised formulations (F7–F9) occupied an intermediate position, generally showing small particle sizes but relatively higher PDI values, indicating that, although Na CMC was capable of yielding fine particles, it was less effective at maintaining a narrow and reproducible size distribution than Carbopol under the conditions employed.The dissolution enhancement observed with the optimised formulation F3 (98.98% release at 60 min, compared with 72.63–89.66% for the remaining formulations) is consistent with the expected consequences of nanosisation: an increase in effective surface area available for solvation, improved wetting by the incorporated surfactant (SLS) and stabiliser, and a probable increase in apparent saturation solubility, in line with the higher measured saturation solubility of F3 (0.892 mg/mL) relative to the other batches. These observations parallel trends reported for other nanosuspensions prepared by nanoprecipitation or related bottom-up methods, in which optimised formulations bearing an appropriately selected polymer/surfactant combination consistently achieved cumulative release in excess of 90–99% within 30–60 minutes, together with comparable particle-size ranges (of the order of a few hundred nanometres) and moderate-to-high negative zeta potentials indicative of adequate colloidal stability.The FTIR and DSC data obtained for the optimised formulation provide complementary evidence that the dissolution enhancement observed is attributable to a physical (particle-size and surface-area) effect rather than to a chemical modification of the drug. The retention of all principal FTIR absorption bands of Ibrutinib in the optimised formulation, without shift or loss, indicates the absence of covalent interaction or degradation of the drug in the presence of the selected stabilisers, while the sharp DSC melting endotherm of the pure drug at approximately 151.4 °C, closely matching the observed capillary melting point (150.2 °C) and the pharmacopoeial range (149–158 °C), confirms that the starting material used in this study was crystalline and of acceptable purity. Taken together, these findings support the conclusion that the drug retained its molecular identity throughout the nanoprecipitation process and that the observed differences in dissolution behaviour arise principally from differences in particle size, size distribution and surface characteristics among the nine formulations.

From a formulation-design perspective, these results reinforce the importance of systematically screening stabiliser type and concentration when developing a nanoprecipitation-based nanosuspension, since the choice of polymer materially influenced not only the physical characteristics of the resulting particles but also their functional in-vitro release performance. The present study is, however, limited to in-vitro characterisation; no in-vivo pharmacokinetic data were generated, and although the observed increase in saturation solubility and dissolution rate is mechanistically expected to translate into improved oral absorption for a dissolution-rate-limited BCS Class II drug such as Ibrutinib, this expectation would need to be confirmed by subsequent in-vivo pharmacokinetic and pharmacodynamic studies. Likewise, although the present dataset establishes the immediate physicochemical and dissolution profile of the optimised formulation, longer-term physical and chemical stability under defined storage conditions was not evaluated in the present dataset and represents an important area for future work.

CONCLUSION

Ibrutinib nanosuspensions were successfully prepared by the nanoprecipitation technique using Carbopol, Ethyl Cellulose and Sodium CMC as stabilising polymers, in combination with PVP K-30 and sodium lauryl sulfate. All nine formulations yielded particles in the sub-micron (nanometre) range (260.4–453.2 nm), with satisfactory drug content and entrapment efficiency. Formulation F3 (Ibrutinib:Carbopol, 140:200 mg) was identified as the optimised batch on the basis of its favourable particle size (341.8 nm), the narrowest polydispersity index (0.43), the highest-magnitude zeta potential (−34.44 mV), the highest drug content (99.63%), entrapment efficiency (98.90%) and percentage yield (94.25%), and the greatest saturation solubility (0.892 mg/mL) and cumulative in-vitro drug release (98.98% at 60 minutes) among the formulations studied. FTIR and DSC studies confirmed the absence of significant drug–excipient interaction, and SEM confirmed the formation of discrete, spherical, nanometric particles. These findings indicate that nanoprecipitation using Carbopol as stabiliser is an effective and technically straightforward strategy for enhancing the dissolution characteristics of Ibrutinib, a poorly water-soluble BCS Class II anticancer agent. However, the improvement in oral bioavailability, therapeutic efficacy and patient compliance implied by these in-vitro results cannot be established from dissolution data alone and will require confirmation through further in-vivo pharmacokinetic and pharmacodynamic evaluation, together with formal stability studies, as the logical next steps in the development of this formulation.

ACKNOWLEDGEMENT

The author gratefully acknowledges the Department of Pharmaceutics, Sri Venkateswaraa College of Pharmacy (SVVCOP), Dharmapuri, for providing the laboratory facilities and instrumentation required to carry out this work. The author also thanks SURA LABS, Dilsukhnagar, Hyderabad, for providing the gift sample of Ibrutinib used in this study.

CONFLICT OF INTEREST

The author declares no conflict of interest associated with this work.

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