Advancements in Liquisolid Compacts Technology Formulation and Characterization

 

Mohammad Faizan, Ismail Moazzam.

Department of Pharmaceutics, Maulana Azad Educational Trust’s Y.B. Chavan College of Pharmacy, Aurangabad 431003, Maharashtra.

 

*Correspondence: md.faizan189070@gmail.com

Article Information		Abstract
Review Article Received: 18/07/2024 Accepted: 2407/2024 Published:26/07/2024   Keywords Carrier coating material, Liquisolid compacts, solubility enhancement    liquisolid, Loading factor.		The liquisolid approach shows promise in addressing bioavailability and solubility issues in medications. The use of organic solvents that are soluble in water, such as glycerine, propylene glycol, or polyethylene glycols, improves wettability and guarantees the molecular dispersion of medications that are insoluble in water. Aerosil-200 is a coating substance and microcrystalline cellulose is a common carrier. Liquisolid compacts have more surface area, better wettability, water solubility, and improved drug release. Using this method, medication suspensions or solutions are turned into dry, pliable, and compressible powders. Evaluations of flow behaviour, wettability, hydrophilicity, solubility, drug content, and analytical methods such as XRD, FT-IR, and DSC are all included in the characterization process. Liquisolid systems present a new and effective option to formulate pharmaceuticals that are both water-soluble and water-insoluble, opening up a route for better medication performance, sustained drug delivery, and greater solubility.

 

INTRODUCTION

One of the technical challenges in developing an appropriate dosage form for effective drug administration is the solubility of many active pharmacological components. In the gastrointestinal tract, the majority of hydrophobic medications classified as sparingly soluble, barely soluble, and very slightly soluble dissolve extremely poorly, resulting in uneven and insufficient absorption. [[i]] Roughly 60% of synthetic chemical entities and 40% of recently created medications are said to have solubility problems. Thus, many pharmaceutical scientists are interested in finding ways to increase the solubility and dissolution of these weakly water-soluble medications as well as their bio availabilities. These medications classified as Biopharmaceutical Classification System Class II (BCS II) are frequently restricted in their bioavailability due to their gastrointestinal tract solubility and dissolution rate. [[ii]]

Current studies have highlighted the efficaciousness of the liquisolid compact approach in improving the solubility of pharmaceuticals with low water solubility and in creating solid dosage forms with instant release. The novel technique known as "liquisolid compacts" is thought to be a viable tactic for reaching this objective. [[iii]] This method has the potential to enhance the solubility of drugs and create solid dosage forms with instant release properties.[[iv]] The primary issue with the formulation development of novel chemical entities and the production of generic drugs is low water solubility.[[v]] The term "liquisolid systems," as used by Spireas, refers to the process of physically blending a liquid with certain excipients known as the carrier and coating ingredients to create a free-flowing, easily compressible, and ostensibly dry powder.[[vi]]In liquisolid systems, a medicine is sorption-deposited into a porous carrier encircled by small coated particles. This process produces a powder that is free-flowing, compactable, and has a dry appearance. This novel method allows for better breakdown of poorly soluble medications and allows for controlled drug release^. [[vii]] Drugs can be carried in a liquid system and distributed throughout the finished product by using non-volatile solvents to prevent liquid evaporation during drug solution/suspension manufacturing. [[viii]]Excipients with strong adsorption qualities and porous surfaces, such as celluloses, lactose, starch, and avicel, fuji Calin, neusilin are used as carriers. Coating materials include silica powders like Aerosil and Cab-o-sil. [[ix]] In liquisolid technology, mesoporous silica has drawn interest for its unique surface features, non-toxicity, and inert qualities, which help improve the solubility of poorly soluble medications. As a molecular sieve, mesoporous silica's high porosity and vast internal surface area allow it to adsorb a sizable amount of liquid. This mesopore network improves bioavailability by increasing dissolving rates. [[x]] Excipients such as disintegrants and super disintegrants are frequently added to solid dosage forms with improved drug release to encourage the formulation's disintegration into tiny fragments in the gastrointestinal fluids. [[xi]]Key benefits of the liquisolid compact technology are low cost, easy processing, and great industrial output potential. It turns out that this is one of the best strategies to improve a drug's bioavailability, dissolution, and solubility^. [[xii]] This approach has promise for enhancing the photostability of susceptible medications in solid dose forms. In this case, the photoprotective properties of particular excipients (coat and carrier) provide an alternative to traditional tablet coatings. [[xiii]]

Using standard procedures to convert high-dose medications into liquisolid tablets less than 1g is impractical. [[xiv]] For compatibility tests, pre-`formulation experiments, such as DSC and FTIR, are conducted on pre-flowing powder stands. Many aspects, including angle of repose, flow properties, solubility studies, and liquid load retention potential, are investigated to optimize water solubility and medication release. With continued research into its possible uses in the pharmaceutical sector, liquidsolid technology appears to be one of the most promising approaches for fostering drug degradation and maintaining drug release.[12]

 

ADVANTAGES OF LIQUISOLID SYSTEMS

Ø  Compared to soft gelatin capsules, liquisolid systems are less expensive formulations.

Ø  Their production is comparable to that of regular tablets.

Ø  By employing the right formulation ingredients, drug release can be adjusted. [[xv]]

Ø  Industrial production's capacity. [[xvi]]

Ø  The number of solid drugs that are water-insoluble can be formed into liquisolid systems;

Ø  The medication has higher bioavailability than traditional tablets.

Ø  The volume of the dissolving media has no bearing on the drug's dissolution from liquisolid compact. [[xvii]]

Ø  Even when a medicine is shaped like a tablet or capsule, it retains its solubilized liquid form, improving drug dissolving and wetting properties.

Ø  The drug is retained in a solubilized liquid state even if it is in a tablet or capsule shape, which increases the drug's wetting qualities and improves drug dissolution.

Ø  Drug release can be adjusted with the right formulation elements. [[xviii]]

LIMITATIONS

Ø  This method is not suitable for the formulation of high-dosage insoluble drugs.

Ø  Adding more carrier to create a free-flowing powder makes the tablet heavier than one gram, making it difficult to swallow.

Ø  Acceptable compression properties might not be reached because the liquid drug might be forced out of the liquisolid tablet during compression, resulting in tablets with an uneven hardness.[18]

Ø  It might not be possible to introduce this technology on an industrial scale and find a solution to the issue of combining small amounts of viscous liquid solutions onto huge amounts of carrier material.

Ø  The solvent nature of hydrotropy is said to be pH-independent, very selective, and does not require emulsification, making it preferable to other solubilization techniques including miscibility, micellar solubilization, co-solvency, and salting in. [[xix]]

Ø  The medicine must be highly soluble in non-volatile liquid media. [[xx]]

Ø  High dosage, water-insoluble, lipophilic medicines are not well suited for formulation using the liquid-solid technique.

Ø  It does not call for the creation of an emulsion system, the use of organic solvents, or the chemical modification of hydrophobic medications.[10]

COMPONENT OF LIQUISOLID COMPACTS

1) Drug

They might not even dissolve in water. The medications used in liquisolid systems should be water insoluble, weakly soluble, or low dose. It needs to be classified as BCS classes II. [[xxi]]

2) Liquid Vehicle

Non-volatile organic solvents that are water soluble, inert, and suitable for oral consumption should be used as the liquid vehicle in liquisolid systems. Propylene glycol, glycerine, polysorbate 20 and 80, PEG 200 and 400, and so on are a few examples of these solvents. The drug's solubility in non-volatile solvent has a major effect on tablet weight and dissolving profile. Because the drug dissolves more readily in the solvent, less carrier and coating material are needed to produce tablets with lower weights. [[xxii]]

                Table 1: Representing Various Reported Non-volatile solvent

 

3) Carrier Material

Carriers with strong liquid absorption capacities and porous surfaces are essential for successful liquisolid compositions. The type of coating material, the viscosity, polarity, and chemical structure of the liquid vehicle, as well as its carrier specific surface area (SSA), are factors that affect liquid absorption. The enhanced flowability, compressibility, and dissolving profiles of microcrystalline cellulose (MCC).[2] 

The quantity of wettability and surface exposure of the drug particles with the dissolving media is ultimately determined by the powder's specific surface area (SSA). Choosing a carrier with a high Specific Surface area is therefore crucial. Table 1 lists the surface areas of several carriers that were tested using the BET Surface Area technique, according to Nokhodchi et al. The unusually high SSA of Neusilin® US2 was shown to improve the powder blend's liquid load factor by a factor of 7. Because Microcrystalline Cellulose and other similar carriers have a low liquid absorption capacity, Neusilin® US2 therefore holds great promise for both achieving a competent dissolution profile and high dose integration for Liquisolid technology.  

Table 2: Surface areas of various powders used as carriers in Liquisolid System [[xxiii]]

 

 

4) Coating Material:

Fine, incredibly adsorptive coating components—which are typically in the form of powder are used in liquidsolid compositions. Notable examples include calcium silicate, Aerosil® 200, Neusilin®, and magnesium alumino-metasilicates. These ingredients are essential to the liquisolid formulation process because they coat wet carrier particles to create a dry, non-adherent, free-flowing powder. They achieve this by drawing excess liquid out of the mixture and absorbing it using adsorbents. One of the main benefits of using Neusilin® as a coating material is that it can reduce tablet weight and boost liquid adsorption capacity greatly when compared to alternatives like Aerosil® 200.[4]

Table 3: Representing the various Reported Coating Material

 

5) Super Disintegrants

These are employed to disintegrate the compacts into smaller fragments. Super Disintegrates: Pulmogel, Sodium Starch Glycolate (SSG), Explotab, Pre-gelatinized starch, Crossprovidone, and Sodium Croscarmellose etc. [18]

 

 

Table 4: Components generally involved in a liquisolid formulation. [[xxiv]]

Excipients Type	Characteristics	Examples
Non-Volatile Solvent	Inert water-miscible, suitable with medication candidate.	glycerine, propylene glycol, polysorbate, tween 20, tween 80, PEG 200,400,600, etc.
Coating Material	incredibly fine and highly adsorptive particles with a positive flow-aiding impact.	Colloidal silicon dioxide     (e.g. Aerosil/Cab-O-Sil) Neusilin Calcium Silicate etc.
Carrier Material	Porous, has a high specific surface area, good flowability, strong adsorption capacity, and good compressibility.	Dibasic calcium phosphate anhydrous, magnesium aluminium silicate, Avicel etc.

 

PREPARATION OF LIQUISOLID COMPACTS

Drug and non-volatile solvent quantities are precisely weighed into a 20- ml glass beaker, and the solvent is heated to dissolve the drug in it. The hot medicament that is produced is used to determine how much carrier and coating material is needed. According to Spiraea’s et al., there are three processes in the mixing.

First Stage: To disperse liquid medication equally throughout the powder, the system is blended for about a minute at a pace of one revolution per second.

Second Stage: In order to allow the medication solution to seep into the interior of the powder particles, the liquid/powder admixture is uniformly distributed out over the surfaces of a mortar and allowed to stand for about five minutes.

Third Stage: Using an aluminium spatula, the powder is removed from the mortar surfaces, and it is then mixed with sodium starch glycolate for an additional 30 seconds, just like in the first step. This makes it possible to compress the final liquisolid formulation. [[xxv]]

Subsequently, each batch was mixed for 30 seconds after the addition of super disintegrant, and then for another two minutes after the addition of lubricant. Using an appropriate punch in a rotating tablet compression machine, the final LS powder formulation was compressed into LSCs. [[xxvi]]

MECHANISMS OF ENHANCED DRUG RELEASE FROM LIQUISOLID SYSTEMS

Liquisolid systems have given rise to several hypothesized methods of increased drug release Three primary processes have been proposed. ^[[xxvii]]

1. Increased drug surface Area:

The drug is still present in powdered form even after the chosen non-volatile solvent totally dissolves the drug particles. Compared to immediately compressible tablets, liquisolid compacts have a larger surface area. The amount of medicine in contact with the dissolving liquid increases with an increase in surface area. If the formulation of the liquisolid compacts has a greater proportion of undissolved drug, drug release will be decreased. In contrast, drug release would increase with an increase in the amount of molecularly distributed drug. [[xxviii]]

Figure 1. Outline of Liquisolid preparation [[xxix]]

 

2. Increased aqueous solubility of the Drug:

In a liquisolid compact, the comparatively modest volume of liquid vehicle is insufficient to raise the drug's total solubility in the aqueous dissolution medium. The amount of liquid vehicle that diffuses out of a single liquisolid particle along with the drug molecules, however, may be sufficient to increase the aqueous solubility of the drug if the liquid vehicle functions as a cosolvent at the solid/liquid interface between the release medium and an individual liquisolid primary particle. [[xxx]]

3.Improved wetting properties:

Wetting of the liquisolid main particles is enhanced by the liquid vehicle's ability to function as a surface-active agent or have a low surface tension. The measurement of contact angles and water rising times has proven the wettability of these systems. It is plausible that the quantity of liquid vehicle diffusing out of a single liquisolid particle in this context. [[xxxi]]

 

                 Fig 2: Wetting property of liquisolid system

FORMULATIONS OF LIQUISOLID COMPACTS

1. In Antihypertensive Class:

Sr NO	DRUG	BCS CLASS	NON-VOLATILE SOLVENT	CARRIER MATERIAL	COATING MATERIL	SUPER DISINTIGRANT	REFERENCE
1	Candesartan	II	PEG -400, PG	Avicel PH 102	Aerosil-200	Cross Carmellose Sodium (CCS)	[[xxxii]]
2	Olmesartan Medoxomil	II	Acrysol EL 135, Plurololeique, Lauroglycol Acconon C-80, Captax 200, Captax 355, PG, PEG 200, PEG400, Capmul MCM& Castor oil.	Avicel PH 102	Aerosol- 200	Cross Carmellose Sodium	[[xxxiii]]
3	Amlodipine besylate and Valsartan	II	Propylene glycol, PEG 400, PEG 600, 0.1N HCl, Phosphate buffer pH 6.8 and Distilled water.	MCC	Aerosil- 200	Cross povidone	[[xxxiv]]
4	Telmisartan	II	Transcutol HP, propylene glycol, PEG 200, PEG 600, Tween 20, and Tween 80	Avicel PH 102	Aerosil- 200	CCS	[[xxxv]]
5	Valsartan	II	Propylene glycol	Avicel PH 102	Aerosil- 200	CCS	[[xxxvi]]
6	Eprosartan mesylate	II	PEG 400	MCC	Aerosil- 200	Sodium starch glycolate	[[xxxvii]]
7	Nifedipine	II	PEG 400, Tween 80	Avicel PH 102	silica gel powder	--	[[xxxviii]]
8	Eplerenone	II	PEG-400	Avicel PH 101			[[xxxix]]

2. Non-steroidal anti-inflammatory drugs (NSAIDs)

Sr NO	DRUG	BCS CLASS	NON-VOLATILE SOLVENT	CARRIER MATERIAL	COATING MATERIL	SUPER DISINTIGRANT	REFERENCE
9	Naproxen	II	Cremophor EL	MCC	Colloidal silica	maize starch	[[xl]]
10	Acelofenac	II	Propylene glycol, PEG 400 and Tween 80.	MCC	Aerosil	Cross povidone, SSG&CCS	[[xli]]
11	Nimesulide	II	PEG 400	MCC, HPMC-E15, Soluble starch	nm- sized silica gel	Sodium Starch Glycolate (SSG)	[[xlii]]
12	Piroxicam	II	Tween 80	MCC	Silica	sodium starch glycolate	[[xliii]]
13	Ketoprofen	II	PEG 400	MCC	Aerosil PH 200	CCS	[[xliv]]
14	Ibuprofen	II	propylene glycol, polyethylene glycol (PEG) 200, cremophor RH 40, tween 80,	MCC	Aerosil 200	sodium starch glycolate, cross povidone	[[xlv]]
15	Celecoxib	II	PEG 200	Avicel	Aerosil PH 101	sodium starch glycolate	[[xlvi]]

 

EVALUATION OF LIQUISOLID SYSTEMS

Precompression Studies Of Prepared Liquisolid Powders

1. Angle of repose (θ):

A funnel approach was used to calculate the angle of repose. A vertically adjustable funnel was used to pour the mixture through until the desired maximum cone height (h) was reached. The angle of repose was computed and the heap's radius (r) measured. It is the angle formed by the pile's heap and base. [[xlvii]]

Where,

               θ=Angle of repose,

               h=H eight of heap and,

              r=Radius of pile.

2. Compressibility index:

Compressibility is the most straightforward method of measuring powder free flow. The compressibility index provides information on how easily a material may be made to flow.

 Where,

             Vb=Bulk volume

             Vt=Tapped volume.

 

3. Hausner’s Ratio [[xlviii]]

 

A crucial factor in figuring out the flow characteristics of powder and granules is Hausner's ratio. This can be computed using the formula that follows.

 

                  

 

 

Differential scanning calorimetry (DSC):

Differential scanning calorimetric analysis (DSC Q20 TA instrument) is used to examine the physicochemical compatibilities and polymorphic alterations of the drug and excipients. For DSC, two milligrams of pure drug samples and liquid-solid compacts are precisely weighed and placed in aluminium pans. The empty pan is sealed and used as a reference. Indium serves as the reference for calibration of the device. At a scanning rate of 140 degrees Celsius per minute, the sample's thermal behaviour is examined over a temperature range of 0 to 200 degrees Celsius. [[xlix]]

 

Fourier Transform Infrared Spectroscopy (FTIR)

 

Investigations of the interactions between drugs and excipients were done using FTIR. Using an IR spectrophotometer (Shimadzu, Kyoto, Japan), the sustained release liquisolid formulation, carrier material, coating material, physical mixture, and active medication were examined. The KBr disc approach was used, and it took three minutes to scan. The 400 cm-1 and 4000 cm-1 scanning ranges were used to record the spectra. ^[[l]] The absence of extra peaks in the formulation and the presence of typical peaks indicate the absence of chemical interactions.

 

Powder X-Ray Diffraction (PXRD)

 

A popular non-destructive analytical technique for determining a powder's crystalline behaviour in a three-dimensional structure is this one. Additionally, the discovery of new medications, stability testing, and final product quality control frequently employ this analytical technique. When developing a liquisolid compact formulation, PXRD is used to evaluate the changes in the physicochemical properties of the drug and excipients. [[li]]

 

Scanning Electron Microscopy (SEM)

 

Field emission gun scanning electron microscopy (FEG-SEM) was used to study the surface and shape characterization of liquisolid powder. Using carbon double-sided tape, the sample was scattered and then attached to aluminium stubs. A high vacuum evaporator was used to sputter coat liquid-solid powder with platinum in an argon atmosphere.

After that, the stump was scanned in a nitrogen atmosphere for 20 minutes within a vacuum chamber. employed a 5 Kv accelerating voltage (LABS) for topological research and characterization. [[lii]]

Contact Angle Measurement

 

The imaging approach is utilized to measure the contact angle of liquisolid tablets in order to analyse their wettability. The most widely used technique, known as the "imaging method," measures the contact angle for a liquid drop that is lying on a level surface of solid material directly. A drop of a drug-saturated solution in dissolving media is applied to the tablet's surface. ^[[liii]] The diameter and height of the sphere drop on the tablet are measured in order to compute the contact angles. The contact angle measurement using imaging method is shown in Figure 3.

 

 

 

 

 

 

              

 

 

 

 

 

 

 

 

 

 

Fig:3 Schematic Representation of Contact Angle Measurement Using Imagin Method

Calculation of Loading Factor:

To determine a powder's flowability and compressibility, the loading factor is computed using the angle of slide measurement for various carriers and coating materials. Different carriers were used to calculate loading factors utilizing a range of After obtaining the drug loading parameters, the amount of coating and carrier ingredients in each formulation was determined by utilizing the flowing formula.

 

 

 

 

The findings demonstrated that less carrier and coating material was required to create flowable powder at increasing solvent viscosities.

 

Table 5: Reported Loading Factor Various Excipients powder with liquid vehicle.

 

 

 

In Vivo Evaluation of Liquisolid Tablets

Two dosage forms, each carrying the equivalent of 20 mg of commercial famotidine tablets, were used in the study.   Liquisolid tablet F14. The 0.571 g liquisolid tablets were made up of 0.458 g Avicel PH 102 and 0.009 g Aerosil 200, which were made with 20% famotidine in PG, or 20 mg of famotidine. The dosage forms were given according to a randomized, cross-over, single-dose design. The volunteers were split up into two groups of three each: Phase I: F1 was given to the first group and F14 LST was given to the second. Phase II: F1 was given to the second group and F14 LST was given to the first. Between the two phases, there was a 14-day washout interval. After an overnight fast, the medication was given in the experimental setup. The individuals received 400 millilitres of water at 7:00 am on the day of treatment, then 300 millilitres of water along with the medication at 8:00 am. Three hours after the dosage form was administered, a regular breakfast was had. Before the dose form was administered, as well as 20, 40 minutes, and 1, 1.5, 2, 3, 4, 6, and 8 hours after the medicine was administered, heparinized venous blood samples were drawn into glass tubes. After gathering all of the samples, the serum was quickly separated from the blood cells using centrifugation at 3000 rpm for ten minutes. It was then frozen at 20 C until analysis. [[liv]] These contradictory findings regarding liquidsolid formulations demonstrated the need for additional in vivo evidence to support the liquisolid tablets' superiority. However, in general, the majority of research demonstrated that liquisolid formulations performed better than their commercial counterparts. [[lv]]

In Vitro Drug Release

The in-vitro drug release analysis of the tablets was carried out using USP type II equipment paddle at 37°C ± 0.5°C using 0.1 N HCL (900 ml) as a dissolution medium and 50 rpm. The dissolution test was utilized to compare liquid-solid compact tablets and marketed tablets. 10 ml samples were taken out and replaced with brand-new dissolving medium at the scheduled intervals. Samples that had been withheld were filtered using a 0.45-m membrane filter.^[48] A calibration curve was used to generate an equation that was used to compute the cumulative percentage of medication release.[45]

Stability of Liquisolid systems with Enhanced drug Release:     

The effects of storage on the crushing strength and release profile of liquisolid compacts were examined in order to gather data on the stability of liquisolid systems. Studies on the stability of liquisolid systems containing polythiazide (40 °C/42 and 75% R.H., 12 weeks), hydrocortisone (ambient conditions, 10 months) [1], carbamazepine (25 °C/75 % R.H., 6 months), indomethacin (25 °C/75 % R.H., 12 months), piroxicam (25 °C/75 % R.H., 6 and 9 months, respectively), or naproxen (20 °C/76 % R.H., 4 weeks) demonstrated that neither the hardness nor the release profiles of liquisolid compacts were affected by storage under various conditions. This suggests that the technology is a promising method for increasing the release rate without compromising physical stability. [[lvi]]

APPLICATIONS

Ø  One effective method for increasing the bioavailability of medications that are water insoluble is the use of liquidsolid compact technology. Liquisolid compacts have been developed from a number of water-insoluble medications that dissolve in various non-volatile solvents.

Ø  A number of medications have been effectively added to liquisolid compacts, according to literature. [[lvii]]

Ø  Long-term This approach has been used to obtain the release of medications that are water soluble, such as propranolol hydrochloride.

Ø  Liquisolid formulations have rapid release rates.

Ø  Liquisolid technique as a promising tool to improve drug photostability in solid dosage forms.

Ø   making them effective for usage with liquid lipophilic or water-insoluble solid medicines. [[lviii]]

Ø  The use of the liquidsolid method can help reduce the impact of pH variations on medication release. The ionization constant (pKa) of the chemical and the pH of the surrounding environment determine how soluble weak acids and bases are. The pH of gastrointestinal fluids therefore has a significant impact on the solubility and absorption of many medications.This results in a considerable level of diversity both within and between medication bioavailability and therapeutic effects.[[lix]][[lx]]

CONCLUSION

This liquisolid technology can be used to create both liquid lipophilic medications and solid pharmaceuticals that are insoluble in water. By choosing the right solvent and carrier, the Liquisolid technique can improve the absorption and dissolution rate of a drug that is poorly soluble, insoluble, or lipophilic. It can also be used to formulate drugs for immediate release, sustained release, or controlled release. Because liquid drugs are intended to be included in powdered form in Liquisolid formulations, their drug delivery mechanisms are comparable to those of liquid-containing soft gelatin capsule preparations. Liquisolid formulations exhibit improved solubility, dissolution, compressibility, flowability, and absorption. Additionally, the method is used to create sustained release systems using hydrophobic carriers rather than hydrophilic ones. Liquid-solid compacts with various formulations show that they have the finest instruments for enhancing medication dispersion.

 

ACKNOWLEDGMENTS

 

Mr. Farhat Jamal (Chairman Maulana Azad Educational Trust) for his motivation and facilities for conducting research work.

 

REFERENCES:

1.        Manogar PG, Hari BV, Devi DR. Emerging liquisolid compact technology for solubility      enhancement of BCS class-II drug. Journal of Pharmaceutical Sciences and Research. 2011 Dec 1;3(12):1604.

2.        Lu M, Xing H, Jiang J, Chen X, Yang T, Wang D, Ding P. Liquisolid technique and its applications in pharmaceutics. Asian journal of pharmaceutical sciences. 2017 Mar 1;12(2):115-23.

3.        Spiraeas S, Sadu S. Enhancement of prednisolone dissolution properties using liquisolid compacts. International Journal of Pharmaceutics. 1998 May 18;166(2):177-88.

4.        Jamkhandi VG. Formulation and evaluation of immediate release tablet of carvedilol using liquisolid compacts technique for solubility enhancement. Asian Journal of Pharmaceutics (AJP). 2016 Sep 10;10(03).

5.        Lohithasu D, Ramana JV, Girish P, Harsha IN, Madhu G, Lavanya K, Sri DS. A latest review on liquisolid technique as a novel Approach. World Journal of Pharmaceutical Research. 2014 Apr 15;3(4):479-93.

6.        Hentzschel CM, Sakmann A, Leopold CS. Suitability of various excipients as carrier and coating materials for liquisolid compacts. Drug development and industrial pharmacy. 2011 Oct 1;37(10):1200.

7.        Vraníková B, Svačinová P, Marushka J, Brokešová J, Holas O, Tebbens JD, Šklubalová Z. The importance of the coating material type and amount in the preparation of liquisolid systems based on magnesium aluminometasilicate carrier. European Journal of Pharmaceutical Sciences. 2021 Oct 1;165:105952.

8.        Javad Zadeh Y, Siahi-Shadbad MR, Barzegar-Jalali M, Nokhodchi A. Enhancement of dissolution rate of piroxicam using liquisolid compacts. Il Farmaco. 2005 Apr 1;60(4):361-5.

9.        Jadhav NR, Irny PV, Patil US. Solid state behaviour of progesterone and its release from Neusilin US2 based liquisolid compacts. Journal of Drug Delivery Science and Technology. 2017 Apr 1; 38:97-106.

10.    Bhattacharyya S, Ramachandran D. Solubility enhancement study of lumefantrine by formulation of liquisolid compact using mesoporous silica as a novel adsorbent. Materials Letters: X. 2022 Dec 1;16:100171.

11.    Vraníková B, Pavloková S, Gajdziok J. Experimental design for determination of effects of super disintegrant combinations on liquisolid system properties. Journal of pharmaceutical sciences. 2017 Mar 1;106(3):817-25.

12.    Sabri LA, Hussien AA. Formulation and In-Vitro Characterization of Solidified Nebivolol Self-Nano emulsion using Liquisolid Technique. Systematic Reviews in Pharmacy. 2020 Mar 1;11(3).

13.    Khames A. Investigation of the effect of solubility increase at the main absorption site on bioavailability of BCS class II drug (risperidone) using liquisolid technique. Drug delivery. 2017 Jan 1;24(1):328-38.

14.    Singh SK, Srinivasan KK, Gowtham Rajan K, Prakash D, Gaikwad NB, Singare DS. Influence of formulation parameters on dissolution rate enhancement of glyburide using liquisolid technique. Drug development and industrial pharmacy. 2012 Aug 1;38(8):961-70

15.    Thakur N, Khokra SL, Sharma D, Thakur NS, Purohit R, Arya V. A review on pharmaceutical application of liquisolid technique. Am. J. Pharmtech. Res. 2011; 1:1-8.

16.    Yadav VB, Yadav AV. Liquisolid granulation technique for tablet manufacturing: an overview. Journal of Pharmacy Research. 2009 Apr;2(4):670-4.

17.    Pawar JD, Jagtap RS, Doijad RC, Pol SV, Desai JR, Jadhav VV, Jagtap SR. Liquisolid compacts: a promising approach for solubility enhancement. Journal of Drug Delivery and Therapeutics. 2017 Jul 15;7(4):6-11.

18.    Deshmukh AS, Mahale VG, Mahajan VR. Liquisolid compact techniques: A Review. Research Journal of Pharmaceutical Dosage Forms and Technology. 2014;6(3):161-6.

19.    Pathak A, Goyal R, Agrawal P, Rajput S, Tiwari G, Shivhare R. A review on liquisolid technology. World J Pharma Res. 2012 Jun 12;1(3):500-12.

20.    Kumar Nagabandi V, Ramarao T, Jayaveera KN. Liquisolid compacts: a novel approach to enhance bioavailability of poorly soluble drugs. Int J Pharm Res Allied Sci. 2011;1(3):89-102.

21.    Varshosaz, J., Ghassami, E., &Ahmadipour, S. (2018). Crystal engineering for enhanced solubility and bioavailability of poorly soluble drugs. Current Pharmaceutical Design, 24(21), 2473-2496.

22.    Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced drug delivery reviews. 1997 Jan 15;23(1-3):3-25.

23.    Gorle AP, Chopade SS. Liquisolid technology: preparation, characterization and applications. Journal of Drug Delivery and Therapeutics. 2020 Jun 15;10(3-s):295-307.

24.    Vogt, M.; Kunath, K.; Dressman, J.B. Dissolution enhancement of fenofibrate by micronization, cogrinding and spray-drying: Comparison with commercial preparations. Eur. J. Pharm. Biopharm. 2008, 68, 283–288

25.    Patel US, Patel KC. Liquisolid technique for poorly soluble drugs. Journal of Scientific and Industrial Research. 2013;2(1):145-59.

26.    Tiong N, Elkordy AA. Effects of liquisolid formulations on dissolution of naproxen. European Journal of Pharmaceutics and Biopharmaceutics. 2009 Nov 1;73(3):373-84.

27.    Kamalakkannan, V.; Puratchikody, A.; Masilamani, K.; Senthilnathan, B. Solubility enhancement of poorly soluble drugs by solid dispersion technique—A review. J. Pharm. Res. 2010, 3, 2314–2321.

28.    Spireas S, Sadu S. Enhancement of prednisolone dissolution properties using liquisolid compacts. International Journal of Pharmaceutics. 1998 May 18;166(2):177-88.

29.    Nokhodchi A, Hentzschel CM, Leopold CS. Drug release from liquisolid systems: speed it up, slow it down. Expert opinion on drug delivery. 2011 Feb 1;8(2):191-205.

30.    Patel UB, Modi DC, Shah DP. Liquisolid compacts: A review. International Journal of Advances in Pharmaceutical. 2017;6(7):110-3.

31.    Bandari S, Mittapalli RK, Gannu R, Rao YM. Oro dispersible tablets: An overview. Asian journal of pharmaceutics, Jan 2008, 2-11.

32.    Reddy et al. Formulation and evaluation of candesartan Immediate release tablets by

using liquisolid Technique.WJPPS,2014,3(2): 2270-2282.

33.    Shailesh T. Prajapati, Hitesh H. Bulchandani,DashrathM. Patel, Suresh K. Dumaniya, and

Chhaganbhai N. Patel. Formulation and Evaluation of Liquisolid Compacts for Olmesartan Medoxomil. Journal of Pharmaceutics.2013,1-9.

34.    Kamagoni K et al. Preparation and enhancement of dissolution rate of amlodipine besylate and valsartan using liquisolid technique. Pharmacie Globale (IJCP) 2013: 06(04),1-6.

35.    Chella N, Narra N, Rama Rao T. Preparation and characterization of liquisolid compacts for improved dissolution of telmisartan. Journal of drug delivery. 2014;2014(1):692793.

36.    Chella N, Shastri N, Tadikonda RR. Use of the liquisolid compact technique for improvement of the dissolution rate of valsartan. Acta Pharmaceutica Sinica B. 2012 Oct 1;2(5):502-8.

37.    Manohar SD, Ramakrishna GA, Bhanudas SR. Formulation and evaluation of liquisolid compact of eprosartan mesylate. World J. Pharm. Res. 2015 Apr 30;4:763-82.

38.    Manohar SD, Ramakrishna GA, Bhanudas SR. Formulation and evaluation of liquisolid compact of eprosartan mesylate. World J. Pharm. Res. 2015 Apr 30;4:763-82.

39.    Khames A. Formulation and characterization of eplerenone nanoemulsion liquisolids, an oral delivery system with higher release rate and improved bioavailability. Pharmaceutics. 2019 Jan 18;11(1):40.

40.    Tiong N,Elkordy AA.Effects of liquisolid formulation on dissolution of Naproxen.Eur J

Pharm Biopharm. 2009:73:373-84.

41.    A. V. Yadav et al. Formulation and Evaluation of Orodispersible Liquisolid Compacts of

Aceclofenac Indian J.Pharm. Educ. Res. 2010, 44(3),227-235.

42.    Kiran Thadkala et al. Enhancement of Dissolution Rate of Nimesulide by Liquisolid Compaction Technique. International Journal of PharmTech Research.2012,4(3), 1294-1302.

43.    Javad Zadeh Y, Siahi-Shadbad MR, Barzegar-Jalali M, Nokhodchi A. Enhancement of dissolution rate of piroxicam using liquisolid compacts. Il Farmaco. 2005 Apr 1;60(4):361-5.

44.    Vittal GV, Deveswaran R, Bharath S, Basavaraj BV, Madhavan V. Formulation and characterization of ketoprofen liquisolid compacts by Box-Behnken design. International journal of pharmaceutical investigation. 2012 Jul;2(3):150.

45.    Regu V, Subudhi BB, Swain RP, Bhattacharjee A, Karna N, Khan AS, Nanda N. Formulation Development and Evaluation of Liquisolid Compacts For Ibuprofen Liquisolid Tablets. Journal of Pharmaceutical Negative Results. 2023 Jan 1:559-71.

46.    Nazem NM, Shokri J, Nourani N, Zangi AR, Lam M, Nokhodchi A, Javad Zadeh Y. Combining liquisolid and co-grinding techniques to enhance the dissolution rate of celecoxib. Journal of Pharmaceutical Innovation. 2023 Mar;18(1):300-9.

47.    The Official Compendia of Standards. United States Pharmacopoeia and National Formulary. Asian Edition. Washington, DC: United States Pharmacopeial Convention, Incorporated; 2000. p. 546-47, 2148-49.

48.    Patric JS. Martin’s Physical Pharmacy and Pharmaceutical Sciences. 5th ed. Lippincott Williams and Wilkins; 2003.

49.    Manogar PG, Hari BV, Devi DR. Emerging liquisolid compact technology for solubility enhancement of BCS class-II drug. Journal of Pharmaceutical Sciences and Research. 2011 Dec 1;3(12):1604.

50.    Hussain Y, Shah MN. Liquisolid Technique: a Novel Tool to Develop Aceclofenac-Loaded Eudragit L-100 and RS-100-Based Sustained Release Tablets. Journal of Pharmaceutical Innovation. 2021 Dec;16:659-71.

51.    Kumari N, Mishra S. A review on solubility enhancement by liquisolid technique as a novel approach.

52.    T. Guan, Y. Miao, L. Xu, S. Yang, J. Wang, H. He, X. Tang, C. Cai, H. Xu, Injectable nimodipine-loaded nanoliposomes: preparation, lyophilization and characteristics, Int. J. Pharm. 410 (2011) 180–187

53.    Bhattacharyya S, Ramachandran D. Solubility enhancement study of lumefantrine by formulation of liquisolid compact using mesoporous silica as a novel adsorbent. Materials Letters: X. 2022 Dec 1;16:100171.

54.    Khaled KA, Asiri YA, El-Sayed YM. In vivo evaluation of hydrochlorothiazide liquisolid tablets in beagle dogs. International journal of pharmaceutics. 2001 Jul 3;222(1):1-6.

55.    Nokhodchi A, Hentzschel CM, Leopold CS. Drug release from liquisolid systems: speed it up, slow it down. Expert opinion on drug delivery. 2011 Feb 1;8(2):191-205.

56.    Kala NP, Shaikh MT, Shastri DH, Shelat PK. A Review on Liquisolid Systems. Journal of Drug Delivery and Therapeutics. 2014 May 15;4(3):25-31.

57.    Madhavi N, Likitha O, Iswariya VT, Swarnalatha KM, Rao TR. A Review on Liqui-Solid Compaction of Solid Dispersion. Journal of Coastal Life Medicine. 2022 Mar 31;10:536-45.

58.    Pathak A, Goyal R, Agrawal P, Rajput S, Tiwari G, Shivhare R. A review on liquisolid technology. World J Pharma Res. 2012 Jun 12;1(3):500-12.

59.    Badawy MA, Kamel AO, Sammour OA. Use of biorelevant media for assessment of a poorly soluble weakly basic drug in the form of liquisolid compacts: in vitro and in vivo study. Drug Deliv 2016;23:818–827.

60.    Ramenskaia GV, Shokhin IE, Savchenko AI, et al. The dissolution test in biorelevant media as a prognostic tool for modeling of drug behavior in vivo. Biomed Khim 2011;57:482–489.