Nano Crystal Technology for Novel Drug Delivery Systems: A Review

Formulating poorly water-soluble pharmacological moieties is currently the most arduous task for formulation experts. An even greater number of recently identified medications with poor water solubility are mostly the result of advancements in high throughput screening techniques. Over 40% of the medications being added to the formulation development pipeline have poor water solubility. Inadequate water solubility of drugs leads to poor bioavailability impacting their therapeutic effect. In order to increase these medications bioavailability, methods for increasing their water solubility are being investigated [1]. In order to improve bioavailability, numerous strategies have been studied. In addition, the majority of these techniques are limited to medications with a certain chemistry (e.g., solubility in particular organic solvents) or a specified molecular size, shape, or conformation (e.g., for molecules to be incorporated into cyclodextrin ring structure). Additionally, the use of surfactants offers a workable substitute, even though their toxicity can be a problem. The bioavailability issues of many poorly water-soluble medications in BCS Classes 2 and 4 have been addressed by the development of the drug into nanosized formulations [2].

"Nanocrystals" are a type of nanosized formulation that consists of nanoscaled drug particles stabilized by an appropriate stabilizer or surfactant. Crystals in the nanometer range, often between a few nanometers and 1000 nm, are referred to as drug nanocrystals. "Nanosuspensions" are drug nanocrystals distributed in an aqueous media. Another feature of the nanocrystals is that, unlike polymeric/lipidic nanoparticles, they are made entirely of medicine and do not contain any carrier component [3]. They are usually prepared by precipitation of the drug from its organic solvent after addition of an aqueous surfactant/stabilizer solution or by using intense particle size reduction techniques tothe drug's macro-sized dispersion while a surfactant/stabilizer is present [5].

Nano Crystals

The early 1980s saw the beginning of modern nanoscience, which is believed to have been sparked by nanocrystals and continues to this day. Solid, pure medication particles with a size in the nanometer range are called nanocrystals. Drug nanocrystals are nanoparticles with a crystal-line character that are crystals in the nanometer range. The definition of a nanoparticle, which refers to the size of a particle to be classified as such, varies depending on the subject [1]. For example, in colloid chemistry, particles are only classified as nanoparticles if their size is less than 100 nm or even less than 20 nm. According to the size unit, nanoparticles in the pharmaceutical industry should be defined as being between a few nanometers and (1000 nm =1 μm); microparticles, on the other hand, have a size of 1–1000 μm.Another feature is that, unlike polymeric nanoparticles, drug nanocrystals are made entirely of the drug; no carrier material is present. These substances are entirely medicinal and are stabilized with polymeric steric stabilizers or surfactants [5] Some of the unique properties of nanocrystals that enable them to overcome barriers are improved saturation solubility, faster rate of dissolution and improved cohesiveness to surface and cell membranes. [6] Nanocrystalline drug technology increases the solubility of hydrophobic medications due to the higher surface area to volume ratio and quicker dissolving rates caused by nanosizing. They are crystallized, as their name would imply, but they may also be partially or completely amorphous depending on how they are made. Drug nanocrystals are scattered in liquid medium to create "nanosuspensions."[8]. To prevent the dispersed particles from settling out of suspension, stabilizers like surfactants or polymeric stabilizers are usually required. The dispersion medium can be water, aqueous solutions, or nonaqueous substances. Depending on the manufacturing procedure, the end product of turning drug microcrystals into drug nanoparticles could be either crystalline or amorphous, especially if precipitation is employed [7]. By reducing the active drug substance's particle size to the nanoscale range while maintaining the drug's crystal form, nanocrystal technology increases the rate of dissolution based on the area. Increased stability: Because a stabilizer is used to stop active medicinal ingredients from re-aggregating during manufacture, these systems are stable [5]. It is possible to stabilize medication nanocrystal suspension in liquid by adding polymers or surface-active-compounds. All poorly soluble medications can be directly broken down into nanometer-sized particles, making them applicable.

Figure: Nano crystal

Figure: Formulation of nano crystals

Figure: Method of production of nano crystals

Bottom-Up Technology:

This technology's basic idea is based on precipitation by the drug is dissolved in a solvent, and the solvent is then added to a non-solvent, causing the precipitation of the small drug particle.

Anti-solvent precipitation

The antisolvent precipitation method dissolves a drug in an organic solvent, then rapidly mixes it with a miscible antisolvent and stabilizer to induce precipitation. Combining high shear or homogenization enhances fragmentation. Baxter’s patented NANOEDGE technology applies shear or thermal energy for friable materials. Rapid supersaturation forms crystalline or amorphous solids stabilized in an O/W system. X‑ray analysis after lyophilization showed 90% carotenoids remained amorphous, highlighting the method’s effectiveness in producing stable nanocrystals [16].

Supercritical fluids Nanoparticles can be produced using supercritical antisolvent, rapid expansion of supercritical solution (RESS), and precipitation with compressed antisolvent (PCA) processes. In RESS, drug solution expands into supercritical fluid, precipitating particles due to reduced solvent power, as shown by cyclosporine nanoparticles (400–700 nm). PCA atomizes drug solution into compressed CO₂, causing oversaturation and precipitation. The supercritical antisolvent method introduces drug solution into supercritical fluid, extracting solvent and inducing supersaturation. However, this approach requires hazardous solvents and more stabilizers or surfactants, limiting its practicality compared to other techniques [19].

Spray-drying: Spray drying is widely used to dry liquids and suspensions by atomizing solution droplets into a cyclone chamber, where hot air rapidly evaporates moisture, forming spherical particles. An atomizer disperses the solution via centrifugal force, while a peristaltic pump controls flow and nitrogen or air maintains pressure. Droplet size reduction increases surface area, accelerating drying. Parameters like concentration, viscosity, spray rate, and temperature can be adjusted to influence particle size, fluidity, and drying speed. This technique has successfully enhanced bioavailability and dissolution rates of drugs such as hydrocortisone and COX‑2 inhibitor BMS‑347070 [19].

Top down: The "Top-down Technologies" are the ways of disintegration and are favoured over the methods of precipitation.

Media Milling: The medication, stabilizer, dispersion medium (often water), and milling media (beads or rods) are all added to a chamber during this process. The movement of the milling media creates shear forces that reduce the size of the drug particles. As the effective surface area of the milling media increases, the number of contact sites available for grinding and dispersing increases exponentially, improving the size reduction capacity.

Bead Milling: Liversidge et al. is a key technique for producing nanosuspensions. It uses high‑shear media mills or pearl mills composed of a milling chamber, shaft, and recirculation system. Drug particles are reduced to nanoscale through impact and shear forces generated by rotating milling media such as glass, zirconium oxide, or polystyrene resin Stabilizers are used to prevent aggregation during the temperature-controlled process. Both micronized and non‑micronized drug crystals can be processed. Coated milling beads minimize contamination. Milling efficiency depends on surfactant type, drug hardness, viscosity, temperature, energy input, and bead size, with milling times ranging from 30 minutes to several days [2].

Dry co-grind

Dry co‑grinding disperses poorly soluble drugs with soluble polymers or copolymers to form stable nanosuspensions. Examples include griseofulvin, glibenclamide, and nifedipine ground with SDS and PVP, producing colloidal particles. Polymers like PVP, PEG, HPMC, and cyclodextrin derivatives enhance solubility by increasing surface polarity and inducing amorphous transformation. This method is fast, cost‑effective, and solvent‑free, improving physicochemical properties and water solubility of poorly soluble pharmaceuticals [25].

High pressure homogenizations

Three key technologies are used when homogenization procedures are used to produce nanocrystals: Microfluidizer technology (Nanojet technology), Piston gap homogenization in aqueous media (Dissocubes® technology), and in water mixes or nonaqueous media (Nanopure® technology) [11].

Homogenization in Aqueous media (Disso cubes) High‑pressure homogenization, developed by R.H. Muller in 1999 and patented by DDS GmbH before transfer to Skye Pharmaceuticals, reduces drug microparticles to nanocrystals using cavitation forces. In this process, drug–surfactant suspensions are forced under pressure through nanosized apertures of piston‑gap homogenizers, such as the APVMicron Lab 40. As liquid flows from a 3 cm cylinder through a 25 μm gap, Bernoulli’s law causes dynamic pressure to rise and static pressure to drop below water’s boiling point. Cavitation occurs when gas bubbles implode, fragmenting particles into nanoparticles [5]. Final particle size depends on homogenizer power density, homogenization cycles, pressure, and temperature [7].

Homogenization in Non-Aqueous Media (Nanopure)

Non‑aqueous homogenization methods, such as Dissocubes and Nanopure, use water‑free media or water mixtures to process suspensions. Oils and fatty acids, with higher boiling points and lower vapor pressures than water, prevent cavitation in Dissocubes. Patents note polymer disintegration at ~80 °C, unsuitable for thermo‑labile drugs. Nanopure technology instead applies “deep‑freeze” homogenization at 0 °C or below, producing results comparable to Dissocubes. Both approaches successfully generate stable nanocrystals, offering alternatives for drugs incompatible with aqueous systems [17].

Nanojet technology

Nanojet, or opposing stream technology, uses a microfluidizer chamber where suspension streams collide under high pressure, generating particle collision, shear, and cavitation forces that reduce particle size. Equipment like M110L and M110S microfluidizers apply this principle. Dearn successfully produced atovaquone nanosuspensions with this method. However, its main limitation is the need for multiple passes through the microfluidizer, which increases microparticle content in the final product [18].

Emulsion solvent diffusion method

The emulsion technique creates nanosuspensions by using volatile or partially water‑miscible organic solvents as the dispersed phase. Drug‑containing solvents are emulsified in an aqueous surfactant solution, then homogenized under high pressure. Dilution with water and further homogenization disperses the solvent, solidifying droplets into particles [6]. Particle size is controlled by emulsion droplet size, while optimized surfactant composition increases drug loading. Though solvents like methanol, ethanol, ethyl acetate, and chloroform were initially used, environmental and safety concerns limit their application. This method has successfully produced nanosuspensions of ibuprofen, diclofenac, and acyclovir [17].

Combination Technology

NANOEDGE® Technology

NANOEDGE technology combines precipitation and homogenization to produce smaller, more stable particles efficiently. It addresses precipitation drawbacks like crystal growth and poor long‑term stability by further homogenizing the suspension to reduce particle size and prevent crystallization [10]. Water‑miscible solvents such as methanol, ethanol, and isopropanol are used for precipitation, though complete removal is preferred for safety. An evaporation stage can eliminate residual solvents, creating a modified starting material. This is then processed via high‑pressure homogenization, ensuring nanosuspensions with enhanced stability, reproducibility, and suitability for pharmaceutical applications [14].

Smart Crystal Technology

This technology was initially developed by PharmaSol GmbH, which Abbott later acquired. It is a group of diverse combination methods from which different iterations can be chosen according on the physical characteristics of the drug (e.g., hardness). The method H42 combines HPH and spray-drying [18] It simply requires a few homogenization cycles to prepare the nanocrystals. The methods H69 (precipitation and HPH) and H96 (lyophilization and HPH) provide amphotericin B nanocrystals with a size range of around 50 nm. S. Kobierski et al. (2008) employed two methods to produce nanocrystals: pre-milling and high-pressure homogenization (HPH). Ball milling and another method were used to make hesperidin nanosuspensions for use in cosmetics [8].

Other Methods

Solvent Evaporation

The emulsion–solvent evaporation method produces nanoparticles by dissolving polymers in volatile solvents and forming emulsions Because of toxicity concerns, safer solvents like ethyl acetate have taken the role of dichloromethane and chloroform. As the solvent diffuses and evaporates, emulsions transform into nanoparticle suspensions. Single (o/w) or double (w/o/w) emulsions are prepared using high‑speed homogenization or ultrasonication, followed by continuous stirring at ambient or reduced pressure. Solidified nanoparticles are recovered via ultracentrifugation, washed, and lyophilized [23]. Particle size is influenced by polymer concentration, stabilizer levels, and homogenizer speed, making this technique versatile for controlled nanosuspension production with improved safety and efficiency [10].

Sono crystallization

Sono crystallization is a cutting-edge technique that uses ultrasonic crystallization to reduce particle size. Sono crystallization is caused by ultrasonic radiation with a frequency range of 20–100 kHz [6]. In addition to increasing the nucleation rate, it is an effective method for controlling the active pharmaceutical ingredient's (API) size distribution and decreasing its size. Ultrasound in the 20 kHz to 5 MHz range was used in most applications [11]. The unfavorable characteristics of NSAIDs, such as their poor solubility and dissolution rate and, consequently, their poor bioavailability, have also been studied.

Melt emulsification

Melt emulsification is the fundamental method for producing solid lipid nanoparticles. Kipp and associates first used the melt emulsification method to create ibuprofen nanosuspensions. It involves four steps. The medication is introduced after the stabilizer-containing aqueous solution [1]. The solution is heated above the drug's melting point and then homogenized using a high-speed homogenizer to produce an emulsion. The temperature is maintained above the drug's melting point during the entire process. In order to precipitate the particles, the emulsion is ultimately chilled. The main factors influencing nanosuspension particle size are the drug concentration, the type and quantity of stabilizers used, the cooling temperature, and the homogenization procedure [23].

Bottom-Up NanoCrySP Technology

Hesperetin nanocrystalline solid dispersions (NSD) can be produced using a contemporary bottom-up method called NanoCrySP technology, which was developed by NIPER researchers like G. Shete and Y. Pawar. Hesperetin and mannitol are mixed in a 1:1 ratio during the spray drying process. Mannitol facilitates hesperetin crystallization by acting as a plasticizer, crystallization inducer, and heterogeneous nucleation site, according to classical nucleation theory. The resultant NSD has nanocrystals with an average crystallite size of 137 nm that are embedded in a mannitol matrix. This technique provides a scalable, solvent-free method for stable pharmaceutical nanocrystals while improving oral bioavailability and pharmacological activity [13].

Characterization Techniques of Nanocrystals

X – Ray Diffraction (XRD): X‑ray diffraction (XRD) is widely used to determine drug crystallinity. Changes in polymorphic form confirm nanocrystal formation. Each crystalline compound produces a distinct XRD pattern, correlated with its pure substance, creating a unique fingerprint that identifies particle structure and composition [8].

Morphological Analysis: Nanocrystals (NCs) are characterized using SEM and TEM to assess size, structure, and morphology. TEM requires wet samples, while SEM needs dried nanosuspensions via lyophilisation or spray drying, which can cause aggregation. Cryoprotectants like mannitol are added to reduce agglomeration during drying. The surface properties like friction, magnetic properties and height are investigated by atomic force microscopy. Additionally, surface plasmon resonance (SPR), a label‑free technique, evaluates nanocrystal surface changes, film dispersion, and particle adhesion, providing deeper insights into NC stability and performance [3].

Thermal Analysis DSC is a crucial method for analysing the thermodynamic characteristics of medicinal nanocrystals. To assess the thermal behavior, the drug's crystallinity and the creation of nanocrystals using different polymers are examined. This discovery is particularly significant for medications with several polymorphic variants.When a solvent or hydrate is heated, thermogravimetric analysis (TGA) helps determine its structure and assess the quality of the sample [6].

Raman Spectroscopy Raman spectroscopy relies on the inelastic scattering of monochromatic laser light, known as the Raman Effect, were photon frequencies shift upon interaction with materials. These shifts reveal low‑frequency rotational, vibrational, and transitional details of compounds. The technique is widely used to characterize nanoparticles and nanostructured materials, including nanocrystals, distinguishing crystalline from amorphous phases and identifying structural transitions. It provides a powerful, non‑destructive fingerprinting method for nanoscale materials, offering insights into their composition, phase behavior, and surface properties critical for drug delivery and advanced nanotechnology applications [25].

FT-IR Analysis:

FT‑IR spectroscopy is used to evaluate drug chemical properties and interactions with excipients. In 2015, Liandong et al. tested spray‑dried curcumin nanocrystals for pulmonary delivery. FT‑IR analysis compared pure curcumin, nanocrystals, and spray‑dried powders, showing that spray drying and milling did not alter curcumin’s chemical properties. The consistency of peak positions relative to the pure drug confirmed structural integrity, indicating that curcumin nanocrystals maintained their chemical characteristics despite processing. This highlights FT‑IR’s value in verifying stability and compatibility of nanocrystal formulations [11].

Particle Size and Polydispersity Index: Particle size and distribution are vital for evaluating dissolution rate, solubility, stability, and therapeutic effectiveness. Microscopy, static, and dynamic light scattering are common methods. Photon correlation spectroscopy (PCS) measures average nanosuspension size but cannot analyze particles above 6 μm. Larger particles are better assessed using low‑angle static light scattering techniques like laser diffractometry (LD) and optical microscopy. LD is particularly reliable for examining mixtures of small and large particles, offering advantages over other approaches in detecting broader particle size ranges and ensuring accurate characterization of nanocrystal suspensions [18].

Solid-State NMR (ssNMR) Spectroscopy:

ssNMR spectroscopy can be used to investigate the kinetic behavior and chemical organization of molecules in crystals. As a result, ssNMR spectroscopy is an essential method for assessing and determining the crystal patterns. Pinon (2015) investigated the effects of three polymorphs and one hydrated condition on samples of the asthma drug theophylline using the NMR technique [17].

Dissolution of nanocrystals

Thermodynamic solubility reflects the drug’s most stable crystalline form in a medium under specific conditions. Nanocrystals, amorphous forms, or metastable polymorphs can temporarily exceed this limit, described as kinetic or perceived solubility. Compared to bulk drugs, nanocrystals show significantly higher solubility and dissolution rates, influenced by particle size and stabilizers. For example, indomethacin nanocrystals dissolved faster than bulk drug, with stabilizers like poloxamers enhancing rates. UV imaging confirmed drug interactions with container materials and filters [1]. Polymers such as PVP and HPMC further improve solubility through co‑solvency and drug‑polymer interactions, reducing supersaturation and crystallization. This “polymer parachute effect” enhances water solubility via electrostatic, van der Waals, or hydrogen bonding, making nanocrystals more effective for drug delivery [6].

Permeation Study

Nanocrystal‑based drug delivery enhances cutaneous and ocular bioavailability for poorly soluble drugs. Because of their increased solubility and dissolution rates, their adhesiveness enhances cutaneous distribution. Skin delivery occurs via concentration gradients and follicular deposition, with ~700 nm particles acting as depots for sustained release. In ocular delivery, nanocrystals increase solubility in lachrymal fluid and improve retention through surfactant‑mediated adhesion. Non‑ionic surfactants are preferred for reduced irritation. Franz diffusion cells are typically used for permeation studies [12].

Particle surface charge

Particle surface charge is a key factor in nanosuspension stability, with higher electrical repulsion improving physical stability. Zeta potential, measured via electrophoretic mobility in an electric field, is the standard quantification method. Colloid titration also assesses charge per unit. In electrolyte solutions, ions adsorb onto particle surfaces, forming the Helmholtz layer. Electrophoresis with laser Doppler scattering calculates particle velocity, typically at 20 V/cm. The Helmholtz–Smoluchowski equation converts mobility into zeta potential, where multiplying observed mobility by 12.8 yields millivolt values under standard conditions, providing reliable stability assessment [11].

Application Of Nano Crystals

The NC method has a lot to offer in the area of pharmaceutical medication delivery in a number of different areas. As a result, examples of the already marketed NC products are given after a presentation of the broad adaptability of NCs to various administration routes and biological applications [1].

Oral drug delivery

The oral route remains the most preferred and safest method for drug delivery, with dissolution being the rate‑determining step for absorption. Nanocrystals enhance dissolution by increasing surface area and saturation solubility, thereby improving drug absorption. Muller et al. refined oral delivery of thermo‑stable drugs using melted PEG (melting point 60 °C), embedding nanocrystals in a solid PEG matrix [21]. These dispersions were milled into powder and compressed into tablets or filled into capsules. This innovative system enables poorly soluble drugs to be incorporated directly into solid dosage forms, significantly improving oral bioavailability and therapeutic effectiveness [17].

 Intravenous drug delivery

Administering a drug via intravenous route provides numerous benefits such as immediate action, reduced dosing and 100% bioavailability. The use of intravenous route is limited because harmful solvent and excipients, which are used during formulation development, are also co-administered with the drug and they can cause serious side effects other than the drug itself. Nanocrystals could be considered as the ideal candidates for intravenous delivery because their developmental processes do not employ excess use of such harmful excipients [24].

Pulmonary drug delivery

The lungs, with a surface area equal to three football fields, enable rapid systemic drug absorption due to lack of hepatic portal drainage. Pulmonary nanocrystals have shown pharmacokinetics comparable to intravenous baicalin, making this route highly effective. However, constant environmental exposure makes lungs vulnerable to pathogens and allergens [4]. Tailoring nanocrystal size improves deep lung deposition. Administration typically requires a nebulizer, which incorporates nanocrystals into inhalable droplets sized 1–5 μm, ensuring efficient delivery and enhanced therapeutic potential [6].

Ocular drug delivery

Ophthalmic drug delivery faces challenges due to the eye’s pharmacokinetic barriers and rapid clearance from blinking and lacrimation, which reduce drug availability and require repeated dosing. Conventional solutions and suspensions often cause poor compliance and side effects. Alternatives like ocular inserts and gels have drawbacks such as irritation and blurred vision. Colloidal systems offered improvements, with Piloplex being the first, binding pilocarpine to nanoparticles [8]. Nanocrystal technology further advanced ocular therapy, enhancing dispersibility of poorly soluble drugs like budesonide, dexamethasone, and hydrocortisone. Ali et al. developed hydrocortisone nanocrystals using microfluidic nanoprecipitation and wet milling, showing extended action and improved bioavailability in rabbits. Forskolin nanocrystals incorporated into an in‑situ gelling system lowered intraocular pressure for up to 12 hours, outperforming conventional suspensions. This demonstrates nanocrystals’ potential to revolutionize ophthalmic drug delivery [22].

Bioavailability Enhancement

Some recently created compounds suffer from low water solubility, which leads to low permeability. By resolving the twin issues of weak solubility and poor permeability across the membrane, nanosuspensions address the issue of low bioavailability [17]. When naproxen nanoparticles are taken orally, the area under the curve (AUC) (0-24 h) is 97.5 mg-h/l, compared to just 44.7 mg-h/l for naproxen suspensions and 32.7 mg-h/l for anaprox tablets. When the gonadotropin inhibitor is administered orally in a traditional dispersion (Danocrine), its absolute bioavailability is just 5.2%; however, when it is administered as a nanosuspension (Danazol), it is around 82.3%. When compared to the traditional commercial formulation, Kayser et al.'s Nanosuspension Amphotericin B shown a notable improvement in oral absorption [25].

Targeted Drug Delivery

Because nanosuspensions' surface characteristics and in-vivo behavior may be readily changed by altering the stabilizer or milieu, they can be employed for targeted administration. The future of targeted drug delivery systems lies in the engineering of stealth Nanoosuspensions (similar to stealth liposomes) using different surface coatings for active or passive targeting of the desired spot. Aphidicolin nanosuspension was developed by Kayser et al. to enhance medication targeting against leishmania-infected macrophages. With an EC (50) of 0.003 mcg/ml, which is roughly 0.16 mcg/ml in the conventional form, he claimed that the nanosuspension formulation had improved activity [16].

CONCLUSIONS

Nanocrystal technology represents a pragmatic and broadly applicable solution to the pervasive problem of poor water solubility in modern drug candidates. By reducing active pharmaceutical ingredients to the nanometer scale and stabilizing them with carefully chosen surfactants or polymers, nanocrystals markedly increase surface area, saturation solubility, and dissolution rate—parameters that directly improve absorption and systemic exposure. A diverse toolbox of manufacturing approaches (bottom‑up precipitation and supercritical methods, top‑down milling and high‑pressure homogenization, and hybrid platforms such as nanoedge® and Smart Crystal®) allows formulation scientists to tailor particle size, crystallinity, and stability to the drug’s physicochemical profile and production constraints. Robust characterization—XRD, electron microscopy, thermal analysis, spectroscopy, particle sizing, and zeta potential—ensures control over polymorphism, morphology, and colloidal behavior, while permeation and dissolution testing link these attributes to in‑vitro and in‑vivo performance. Despite clear advantages in dissolution, permeability, and adhesiveness, nanocrystal development must address challenges including physical instability (aggregation, Ostwald ripening), dose uniformity, potential long‑term toxicity, regulatory complexity, and cost. Successful translation therefore depends on judicious stabilizer selection, scalable process design, and comprehensive safety and stability evaluation. In summary, nanocrystals offer a powerful, adaptable platform to rescue poorly soluble drugs and enhance therapeutic outcomes, but their promise will be realized only through integrated formulation science, rigorous characterization, and careful risk‑benefit assessment.

REFERENCES

1. McGuckin, M. B., Wang, J., Ghanma, R., Qin, N., Palma, S. D., Donnelly, R. F., & Paredes, A. J.Nanocrystals as a master key to deliver hydrophobic drugs via multiple administration routes. Journal of Controlled Release. 2022;3(65):334-353.
2. Phattalapol Lhaglham,Luksika Jiramonai,Yaru Jiaet.al. Drug nanocrystals: Surface engineering and its applications in targeted delivery. iScience2024; 111185(4): 1-27.
3. Alok Vishwakarma, Sheela Yadav, Indira parab. Nanocrystals in Drug Delivery: An Innovative Approach. International journal of pharmacy and pharmaceutical research 2022; 24(1):11-23.
4. Mahalakshmi A, Deattu N,Sunitha P.G, Kokila E, Dhanesh Kumar M. R, ChandiniV.S. A Complete Overview of Nanocrystals in Pharmaceuticals. International journal of pharmacy and pharmaceutical research. 2024;24(2): 112-121.
5. Vaishnavi G Karule, Jitendra A Kubde, Pooja R Hatwar, Ravindra L Bakal, Gayatri J. Khanderao. Nanocrystals: The Building Blocks of Nanotechnology – A Comprehensive Review. Asian Journal of Pharmaceutical Research and Development. 2025; 13(1):84-94.
6. Tuğba GÜLSÜN,Neslihan GÜRSOY R, Levent ÖNER. Nanocrystal Technology for Oral Delivery of Poorly Water-Soluble Drugs. J. Pharm. Sci.2009; 34(4):55–65.
7. MirzaR. M, AhirraoS. P, KshirsagarS. J. ANanocrystal technology: to enhance solubility of poorly water-soluble drugs.Journal of Applied Pharmaceutical Research 2017; 5 (1): 1 – 13.
8. G. Sivanathan et al.Pharmaceutical Nanocrystals: An Extensive Overview. International Journal of Applied Pharmaceutics.2024; 16(6): 1-9.
9. Mishra Rakesh, DharwadSagar, Aher Akash, DhokalePrajakta. Nanocrystals a comprehensive review on formulation and application perspectives. Journal of medical pharmaceutical and allied sciences. 2023;12(3): 5806 – 5816.
10. Abhishek Soni, Rajender Guleria, Ayush Thakur and Komal Bhardwaj. Nanocrystal as Drug Delivery System. Wjpls. 2024;10(3):52-162.
11. Dr. P. Premkumar, Jency Abraham, Nikhila M. Nair, Dr. Shajan Abraham and Gomathi A. R. A comprehensive review of drug nanocrystals: its formulation methods and characterization techniques. Wjpls. 2025; 11(3):24-41.
12. Pujitha R, Daisy chellakumari s, Devi damayanthi R, Aakash N S andAswin kumar A M. Engineered Nanocrystals for Poorly Soluble Drug Delivery: A Review. Indian J Pharm Sci 2024;86(3):742-754.
13. Praeeth siddharth, Rajeswari A.V.S. Overview of nanocrystals. IJCRT.  2023;11(4):98-105.
14. . Digambar premlal rahangdale, diksha bhimte, Nanocrystals in cosmetics and in cosmeceuticals by topical delivery: review. IJCRT, June 2025;13(6):781-795.
15. Jolly A, Balasubramaniam D, Kunnambathu K, Nair SK. A Review on Improved Drug Performance of Nanocrystals Formulations. International Journal of Drug Delivery Technology. 2022;12(4):1901-1904.
16. Jyoti Malik, Anurag Khatkar, Arun Nanda.A Novel Technique of Solubility Enhancement: Nanocrystals. International Journal of Innovative Science and Research Technology. December – 2023;8(2): 851-862.
17. Manting Ji1, Li Long, Sijia Xiong, Zhongqiu Liu, Jun Luo, Dan Liu. Nanocrystalline Drug Delivery Systems for Natural Compounds: Progress, Challenges and Future Opportunities.International Journal of Nanomedicine. 2025; 20(1): 11315–11339.
18. Barmala Prashanth, SK. Sushma Taj, et.al.A review on nanocrystals: applications, preparation, characterization and patented drugs. JETIR March 2025;12(3): 774-787.
19. Sumedh Paralkar, Yogesh Thorat. A review on nanocrystals: a novel drug delivery system. JETNR2024;2(4):240-257.
20. Hira D. Khade, Sonali S. Sonawane. Nanocrystal in Drug Development: Regulatory Perspective and Emerging Pharmaceutical Innovation.International Journal of Pharmaceutical Research and Applications.Jan-Feb 2025;10(1):53-63.
21. Jens-Uwe A H Junghanns Rainer H Müller. Nanocrystal technology, drug delivery and clinical applications. International Journal of Nanomedicine 2008; 3(3):295–309.
22. Aijaz A Sheikh, Amol J Giri*, Arif Sheikh, RH Kale, KR Biyani. Nanocrystal Technology, Characterization and Pharmaceutical Applications. Int J Pharm 2021; 11(11): 7-12.
23. Dhananjay Panigrahi, Pratap Kumar Sahu, Suryakanta Swain, Rajan Kumar Verma. Quality by design prospects of pharmaceuticals application of double emulsion method for PLGA loaded nanoparticles.SN Applied Sciences 2021;3(638):1-21.
24. Manasi M. Chogale, Vinod N. Ghodake and Vandana B. Patravale. Performance Parameters and Characterizations of Nanocrystals: A Brief Review. Pharmaceutics 2016;8(26): 1-18.
25. Sunita Dahiya.Applications of nanocrystals in drug delivery: an overview. Bulletin of Pharmaceutical Research 2018;8(2):159, 1-9.