Development of Liquisolid Compacts: An Approach for Dissolution Enhancement of Poorly Aqueous Soluble Drugs

Abstract

Solubility plays a key role to achieve desired concentration of drug in systemic circulation and show its pharmacological action. An approach of liquisolid technique, developed by Spireas, was employed for the dissolution enhancement of poorly aqueous soluble drugs. Initially, liquid medication (liquid drug or drug solution or suspension in hydrophilic liquid vehicle) is transformed to free-flowing, non-sticky, compressible powder by the addition of suitable carrier material and coating materials for the development of liquisolid compacts. The postulated mechanism for enhanced solubility was improved wettability of drug and enhanced surface area of molecularly dispersed drug in the liquid environment. Pre- and post-the compression tests were performed for the developed liquisolid compacts to obtain optimized formulation. For the optimized compacts, FTIR and DSC studies were performed for determining drug-excipient compatibility; SEM and PXRD studies were performed to study the solid-state characterization. Furthermore, accelerated stability studies were performed for optimized liquisolid compacts for 6 months according to ICH guidelines and the results were compared with freshly prepared formulations. In conclusion, liquisolid compact formulation was proved to be safe, economic and alternative approach to formulate solid oral dosage forms of poorly aqueous soluble drugs.

1. Introduction

Oral route is considered as the easiest, convenient and most frequently preferred route for the administration of pharmaceutical dosage forms. Drug solubility is the most important key factor to achieve desired concentration of drug in the systemic circulation and show its pharmaceutical action. The poor dissolution properties of non-aqueous soluble drugs possess major challenge for researchers in pharmaceutical field in the course of development of solid dosage forms intended for oral administration. The development of several methods during the past few years includes the application of pro-drug and drug derivatization processes, micronization, co-precipitation, salt formation, solid dispersions, inclusion complex formation, lyophilization, micro-encapsulation, incorporation of drug solutions into soft gelatin capsules, self-emulsifying drug delivery systems, etc. In order to increase drug dissolution rate profiles, powder solutions are also designed that contain liquid medications in powdered form.

The rate of oral absorption is frequently regulated by the rate of dissolution in the GIT, in case of Biopharmaceutical Classification Class II drugs (low soluble and high permeable drugs). Therefore, solubility and dissolution rate characteristics of drugs are most important determinants of their oral bioavailability, together with permeation [1]. Hence, the notion of powdered solutions enables the creation of moderately flowing powders from liquid medications or drug solutions obtained by admixing drug solutions or liquid pharmaceuticals with selected powder excipient. Similar methods have been employed by certain researchers to improve the drug release patterns of numerous water-insoluble medicines.

The most recent, modern solubility enhancement approach known as liquisolid (LS) technique or “Powder Solution Technology” introduced by Spireas and Bolton, has been employed to develop rapid release solid dosage forms for water-insoluble or poorly water-soluble drugs [2]. The powdered forms of liquid medications produced via liquisolid process are thought to flow smoothly and also possess compressible nature. The liquid medication can be turned into dry (moistureless), non-sticky powder that can be easily flowable and compressible by simple mixing with chosen carriers, coating excipients [3]. In this method, the medication is dissolved in solvent followed by admixing with powder excipients and administered as solid dosage form. In this instance, the medication has been entirely molecularly distributed. As a result, insoluble or poorly water-soluble pharmaceuticals are anticipated to have improved dissolution rate characteristics and, consequently, higher bioavailability due to notably improved wetting capabilities and increased drug surface area accessible for dissolution.

2. Liquisolid technology

In order to create a “liquisolid powder system,” a non-volatile solvent is first used to prepare either a lipophilic liquid medication or a drug solution/suspension of a water-insoluble or poorly aqueous soluble drug. This substance is referred to as “liquid medication.” Additionally, it is transformed into easily compressible and freely flowing powders by mixing with excipients such carrier and coating ingredients. Liquid medication is combined with a carrier material (Avicel PH 102) having good absorption properties and coating material (Aerosil 200) having high adsorptive properties to obtain non-sticky, free-flowing readily compressible powder. It is further mixed with disintegrants to form immediate release compacts. The liquisolid (LS) powder can be further transformed to conventional solid dosage forms in which they can be compressed to compacts or encapsulated into hard gelatin capsules. The compacts so obtained are termed as liquisolid compacts (LSCs). Increased solubility, wettability, and drug surface area accessible for dissolution from the LSCs are thought to be the causes of the increased drug release rates [4]. However, the features of the medication and the different excipients employed in the formulation play a major role in determining the drug release profile. Therefore, using the LS approach, formulations that may either accelerate or delay the release of the medicine can be created by changing any one of these excipients. The novelty of the current study is application of liquisolid technique for the preparation of drug loaded tablets known as liquisolid compacts, which showed higher drug release profiles compared to that of directly compressed tablets, especially in case of poorly aqueous soluble drugs.

2.1 Constitution of LS formulation

The LS formulations contain some key constituents such as

1. Lipid liquid drug, solution or suspension of drug in hydrophilic vehicle,

2. carrier excipient, and

3. coating excipient

2.1.1 Non-volatile solvent

The non-volatile solvents should be able to solubilize the lipidic drug to the greatest extent, be inert, have a high boiling point, be water-miscible by nature, and not be excessively viscous. In the LS formulation, these hydrophilic solvents serve as a binding agent. Propylene glycol (PG), polysorbate 80, and polyethylene glycol (PEG) are a few examples of hydrophilic non-volatile solvents that are employed in LS formulations [5].

2.1.2 Carrier materials

The majority of liquid absorption is facilitated by carrier materials, which are typically porous materials with great absorption capabilities. These can maintain appropriate flow and compression properties while containing only a limited or fixed volume of solvent. However, an excessive rise in the carrier material’s moisture content causes a deterioration in the powder flow properties. Various MCC grades, such as Avicel PH 101, PH 102, and PH 200, are examples of carrier materials [6].

2.1.3 Coating materials

The coating materials should have tiny, highly adsorbent particles that help to cover the wet surface of the carrier particles and retain the powder’s flowability. Finally, complete adsorption of surplus liquid results in non-adherent, dry-looking powder. It is necessary to coat the surface with coating ingredients such as lactose, starch, syloid, aerosil 200, and silica (Cab-O-Sil M520) [2]. In addition to these, new coating materials with high adsorbent qualities as Sylysia (amorphous silica gel) and Neusilin (magnesium aluminum metasilicate) can also be employed.

2.1.4 Additives

It appears that the release of the drug is influenced by the process of disintegration of solid dosage forms. Therefore, disintegrants are typically added to LSCs to enable rapid disintegration. Examples of super disintegrants are low substituted hydroxypropyl cellulose (HPC), cross carmellose sodium, starch glycolate sodium, and crosspovidone [7]. In some instances, LS systems that typically function as a release retarding agent are supplemented with an additive called HPMC in order to prolong medication release [8]. Figure 1 depicts the diagrammatic picture of the creation of the LS system.

Figure 1.

Diagrammatic representation of formation of LS system.

2.2 Various forms of LS systems

1. Based on the type of liquid medication, the LS systems are divided into four categories.

   1. Powdered liquid drugs

   2. Powdered drug solutions

   3. Powdered drug emulsions

   4. Powdered drug suspensions

2. Based on the formulation technique used, two different types of LS systems are identified.

   1. LS compacts

   2. LS microsystems

The two main formulation elements of LSCs are liquid medicine and powder substrate. The major components of the powder substrate are: (a) carrier particles that are preferably big and porous to improve compression; (b) coating material particles that are ideally very fine and highly adsorptive to improve flow.

The schematic representation of various steps involved in preparation of LS formulations is shown in Figure 2.

Figure 2.

Representation of several stages involved in development of LS formulations.

The amounts of various excipients required for the formulation of powder solutions are predicted using a novel mathematical model expression [9]. The absorbate molecules diffuse through the absorbent until they are eventually consumed by the powder particles inside their bulk, which causes the liquid to be absorbed. Adsorption is the phenomena where liquid is not really absorbed and the molecules merely cling to the solid’s accessible surface, both internal and external, rather than being disseminated throughout the solid’s interior. However, sorption is a mechanism where simultaneous occurrence of both of these processes occur which majorly depends on powder characteristics.

2.3 Mechanisms for enhanced drug release in LS systems

The mechanisms for enhanced drug release in LS systems include.

1. enhanced drug surface area

2. enhanced aqueous solubility

3. enhanced wettability

2.3.1 Enhanced drug surface area

Even if the drug particles are totally dissolved in the preferred hydrophilic non-volatile solvent in the LS system, the drug is still present in the powder substrate, either in molecularly distributed or completely solubilized state. As a result, when compared to directly compacted tablets (DCTs), the surface area of the drug in LS systems is substantially higher. However, when the drug content rises, the solubility limit rises with it. Hence, as the amount of undissolved drug in the liquid carrier increased, the rate of drug release decreased. Furthermore, the rate of drug release increases along with the proportion of molecularly dispersed drug (FM). Spireas’ percentage of the molecularly dispersed drug is the ratio of drug solubility (Sd) in the liquid vehicle to the genuine drug concentration (Cd) in the liquid vehicle transported by each system (FM). It can be calculated using Eq. (1).

$$\mathrm{FM}=\frac{\mathrm{Sd}}{\mathrm{Cd}}$$E1

where, FM is equal to 1, in case if S_d ≥ C_d.

2.3.2 Enhanced aqueous/water solubility of drug

A small volume of liquid vehicle in the LS formulation may not be sufficient in the case of the LS system to entirely solubilize the medication and increase drug solubility in dissolution medium. The solvent diffusing out of an LS particle is sufficient to increase the solubility of poorly aqueous soluble drugs in the dissolution medium at the interface microenvironment of the solid particle and liquid carrier, which is the most likely explanation for the increase in aqueous solubility of poorly aqueous soluble drugs [2]. It’s also feasible that a small amount of the liquid carrier diffuses with the medication from the total amount, acting as a co-solvent to boost the drug’s solubility in water.

2.3.3 Enhanced wetting properties

In the instance of the LS system, the wetting property is explained by measuring the contact angles as well as the water rising times. By lowering the interfacial tension between the powder/tablet surface and the dissolution medium, a non-volatile liquid vehicle aids in the wetting of drug particles in the system. The low contact angle of LSCs compared to conventional tablets proves improved wettability. The wettability of the LS system is improved by lowering the interfacial tension when the liquid vehicle acts as a surfactant. Water growing times and contact angles were used to demonstrate the wettability of the LS system.

By measuring the contact angles and the water rising times in the case of the LS system, the wetting property is described. A non-volatile liquid vehicle facilitates the wetting of drug particles in the system by reducing the interfacial tension between the surface of the powder or tablet and the dissolving media. The superior wettable quality of LSCs is demonstrated by their low contact angle when compared to traditional tablets. When the liquid vehicle functions as a surfactant, the interfacial tension is reduced, which enhances the wettability of the LS system. Water growth times and contact angles were employed to demonstrate the wettability of the LS system.

2.4 Parameters affecting LS formulations

2.4.1 Basis of selection of excipients in LS technology

The LS technology majorly deals with the selection of suitable carrier and coating materials that are mainly responsible for loading of drug in the liquid medication. This may be liquid drug or suspension of drug in a solvent or a solution of drug in suitable liquid (non-volatile) vehicle. This is further adsorbed on the porous carrier material. A liquid layer starts forming on the surface of the particles, when once the carrier material is saturated with liquid, a moist or sticky blend is formed [10]. Dry and free flowing and compressible powder is obtained upon addition of dry coating material that physically exists in a very fine powder, instantly adsorbs fine layer of drug solution over the carrier material. Various forms of microcrystalline cellulose (such as MCC, Avicel PH101, Avicel PH102) are used as carrier materials and mostly amorphous silicon dioxide is used as coating material. Application of LS technique to poorly aqueous soluble drug enhances the drug release due to increased surface area of the drug, that in turn lead to increased solubility and improved wettability of the drug particles. The LS technology may also be applied to prolong the drug release. According to the principle, sustained release or extended release dosage forms provide desirable therapeutic plasma levels which are maintained throughout the therapy. It has been stated that usage of hydrophobic carriers like Eudragit® RL and RS instead of hydrophilic carriers or by addition of a matrix forming polymers like HPMC, sustained release formulations are developed. It was observed that the enhancement in solubility or release characteristics has been successfully improved in case of low dose poorly water-soluble drugs by the application of LS technology. The drug release rate is exactly proportional to the percentage of molecularly (FM) dispersed drug in the liquid vehicle, according to the main concept of LS technology [11].

It is obvious that only a definite amount of powder can absorb or absorb a limited volume of non-volatile solvent to preserve acceptable flow and compression properties. Hence, high amounts of carrier and coating materials are required in case of large volume of liquid medication if high dose drug is used. This result in increase in weight of the tablet eventually leads to formation of bulky tablet. Hence it is required to minimize tablet weight and increase the liquid adsorption capacity. By adding carrier and coating materials or binding agents to the liquid medication with a high specific surface area (SSA) liquid adsorption capacity is obtained. Therefore, higher the SSA of the carrier material, higher will be the liquid load factor. It has been stated that the liquid adsorption capacity of the granular cellulose that is experimental grade exhibits SSA of 24.22 m²/g which is higher than that of microcrystalline cellulose (MCC). Similarly, carrier materials such as Avicel PH102(SSA = 1.10 m²/g) and Avicel PH 101 (SSA = 1.07 m²/g) have been frequently used in the studies due to their higher SSA values. Moreover, it has to be highlighted that the physicochemical characteristics such as viscosity, polarity, lipophilicity and chemical structure of the liquid used for solubilizing or suspending the drug cannot be ignored which could also affect the adsorption capacity of both the carrier and coating materials. Subsequently, the liquid adsorption capacity of a blend of carrier and coating material not only depends on their SSA, but also depends on the liquid vehicle involved.

2.4.2 Ratio of carrier and coating material (R) importance

The pre-compression properties and drug release characteristics of LS systems increase from 5 to 1 to 50 to 1 for excipient ratios denoted by R. The reciprocal of the powder excipient ratios (1/R) and the liquid load factors (Lf) have a linear connection. The powder excipients ratio R affects the dissolving rate profiles of LS systems, with results visible within 5 minutes of the dissolution process against R values in the 5 to 20 range. At powder excipients ratios >20, the dissolving rates have risen proportionally to R until they reached an obvious maximum plateau. Lower R values should indicate medication dissolution patterns that are less than ideal. Increases in R excipient ratios cause a modest drop-in dissolution rate until the maximum degree of dissolution is attained at R values of 35 to 45. The R values greater than 50 indicate that the drug solution was embedded during the formulation process.

Carrier agents are usually able to absorb the solvent in their interiors of matrices. The production of dry-looking, non-sticky liquid pharmaceuticals necessitates large quantities of these carriers. Due to its huge specific area in comparison to other carriers such as lactose and starch, Avicel PH 102 outperformed the others [12]. As a result, the unit size of LS tablets may vary depending on the composition of the carrier material. The more uniformly the drug is adsorbed on the coated material or absorbed into the carrier material, the higher the concentration of Avicel PH 102. The strength and cohesiveness of the LSCs are provided by the H-bonds on the cellulose molecules in Avicel PH 102. Compression transforms them plastically, creating a potent compact [13].

A surface-active substance called polysorbate 80 aids in drug particle wetting by lowering the interfacial tension between the LSC surface and the dissolving solution. As a result, it has been discovered that one of the primary explanations for an increase in dissolving rate is an increase in the wetting qualities of LSCs created by the dissolution media. More uniform drug distribution in the carrier medium was indicated by higher R values, which ranged from 30 to 60 [14].

2.5 Advantages and limitations of LS technique

2.5.1 Advantages of LS technique

1. Maximum drugs belonging to BCS class II can be formulated into LS systems.

2. Improved dissolution profiles (in vitro and in vivo drug release) and enhanced bioavailability for LS formulations can be achieved when compared to conventional dosage forms.

3. Cost-effective method, since the production costs are lower than those of soft gelatin capsules.

4. Formulation of drug either in a tablet dosage form or encapsulated dosage form is possible.

5. Greater surface area of drug will come in contact with the dissolution medium.

6. The LS systems can be developed as immediate release or sustained release dosage forms.

7. In case of optimized sustained release for water insoluble drugs, LS tablets and capsules show constant dissolution rates with zero order release kinetics equivalent to osmotic pump technology and laser-drilled tablets.

8. It is also used in the development of controlled drug delivery systems.

9. The release of drug can be altered using suitable excipients or additives in the LS formulation.

10. The drug is available in molecularly dispersed state in the formulation.

11. The LS formulations can also be produced in industrial scale.

12. Color can be added into liquid vehicle for achieving uniqueness of final product.

13. Lesser excipients can be used in LS formulations when compared to other formulations like solid dispersions.

14. This technique omits the process approaches such as nanonisation, micronization techniques.

15. A number of poorly water-soluble and nearly water-insoluble drugs (ex-Digitoxin, Hydrocortisone, Prednisolone) are formed into LS systems using the new formulation-mathematical model.

16. Because the drug is present in solution form, better availability is attained when a poorly water- soluble agent is orally delivered.

17. The LS powder system available in solubilized liquid state causes increase in wetting nature of drug which further increases dissolution of drug.

2.5.2 Limitations of LS technique

1. One of the major problems with this technique is formulation of high dose lipophilic drugs into LS tablets and hence it is not applicable for the formulation of insoluble drugs with high dose. The technology has been shown successful and employed for low dose water-insoluble medications.

2. High amounts of carrier and coating materials are required to maintain acceptable flowability and compatibility for LS powder formulation. Since these drugs require large quantities of liquid vehicle which increases tablet weight above 1gm which makes them difficult to swallow. On the other hand, using traditional tablet procedures, it is difficult to convert a high dose tablet to a low-dose tablet with a weight of less than 50 mg. Several techniques have been proposed to overcome the problem mentioned above.

For example, adding some of the additives like PVP and PEG 35000, to the liquid medications ultimately increase the viscosity of liquid medication and further may decrease the quantity of carrier and coating material used in formulation development. Modern carrier and coating materials like Neusilin and Fujicalin also have greater specific surface areas (SSA), which results in increased absorption capacities.

1. This technique is only applicable for water insoluble, poorly water soluble and lipophilic drugs.

2. These LS systems require maximum solubility of drug in the hydrophilic non-volatile solvents. It was obvious that acceptable compression properties may not be achieved since during the compression process, there may be chance that liquid drug squeeze out of the LS tablet consequential in tablets of unsatisfactory hardness.

3. It needs more efficient excipients with higher adsorption capacities a smaller tablet size to improve LS formulations.

4. High solubility of the drug in liquid vehicle is prerequisite to prepare liquid solid systems [15].

5. This method of dispersing large amounts of carrier material with small amounts of viscous liquid solutions may not be feasible on large industrial scale.

2.6 Applications of LS technique

2.6.1 Dissolution and solubility enhancement

To overcome the limited solubility of drugs in pharmaceutical area, these are formulated as LS tablets. Basically, the method of preparation of LS tablets and the effect of various formulation and processing variables on the preparation and release properties of LS tablets are studied. This technique is proved and successfully applied for low dose drugs up to 50 mg only. In case of LS tablet, formulation of high dose water insoluble drugs is a limitation. Furthermore, by adding materials like PVP to liquid medications, only a small amount of carrier is needed to generate a dry powder with good flow ability and compatibility.

2.6.2 Flowability and compressibility

LSCs possess acceptable flowability as well as compressibility properties. They are prepared by mixing or simple blending with selected powder excipients such as the carrier material (ex. cellulose, lactose, starch) and the coating materials (ex. silica). In such LS powder systems, the drug exists in form of molecular state of subdivision. These LS systems were also free flowing, non-adherent and dry looking powders. Microcrystalline cellulose (compression enhancer) can be used in the LS problem of ‘Liquid Squeezing Out’ phenomenon whenever observed. Hence, in this system liquid medication is admixed with the excipients and then compressed into tablets. It was also showed that, lesser the drug concentration in the liquid medication, rapid is the release rates. If the drugs are present in high concentration in LS system, they tend to precipitate within the polymers pores.

2.6.3 Designing of sustained release tablet

Several ways have been explored to achieve this goal, including coating with specific materials, preparing a salt variant of the drug, and incorporating drugs into hydrophobic carriers. Hydrophobic carriers like Eudragit RL and RS are used to develop sustained release LS systems. The LS formulations can give both rapid release and sustained release of drugs. Sustained release propranolol hydrochloride (water soluble) by the use of LSC technique was developed [6]. LS method can also be employed to design controlled release of tablets.

2.6.4 Bioavailability improvement

In the solid powdered solution and LS systems drug is present in solution form or almost molecularly dispersed state. As a result of the large increase in wetting properties, the surface area of drug accessible for dissolution, the LSCs of non-aqueous soluble substances are expected to have better drug release properties. As a result, bioavailability is enhanced.

2.7 LSCs formulation development

LSCs are the compressible pulverized forms of the liquid medications containing drugs. These are prepared as a result of compression of LS powder systems containing lipophilic drug, carrier and coating materials.

2.7.1 Formulation design for LSCs

While developing the LSC formulations the following components should be incorporated.

Non-Volatile solvents: Poly Ethylene Glycol (PEG)-200. PEG- 400, PEG- 6000, PEG- 4000, Propylene Glycol (PG), Polysorbate80, Tween–80 etc. Addition of PVP to liquid medication, may lead to production of dry powder formulations comprising liquid with a high drug concentration.

Carriers: Avicel RTM 105, Avicel PH 102 granular Microcrystalline cellulose (MCC) grade, Avicel PH 200 coarse granular MCC grade, lactose and starch. MCC has granular grades with fine particle sizes, which results in good compression capabilities for tablet manufacture.

Super Disintegrates: Sodium starch glycolate (SSG), Crospovidone, croscarmellose sodium (CCS).

Coating Materials: Aerosil PH 200, Colloidal silica, Cab-O-sil RTM M5, Sylysia (amorphous silica gel) and Neusilin (magnesium aluminum metasilicate).

Initially, the saturation solubility studies for drug will be performed in various hydrophilic solvents such as polyethylene glycols (PEG 200, PEG 400, PEG 600); propylene glycol (PG); Span 80; glycerine; Tween 80; Span 20; Tween 20; etc. Saturated drug solutions were obtained by addition of excess drug to each 5 ml solvent taken in screw cap vials. After sealing, the vials were kept on rotary shaker under constant vibration at 25°C and shaken for about 72 hrs. Afterwards, sample aliquots were taken and further filtered. Later, filtrate was diluted appropriately with distilled water and drug content was analyzed using UV–VIS spectrophotometer. The liquid vehicle showing maximum solubility for drug was finally selected as solvent to prepare liquid medication which is further transformed to liquisolid compacts by the addition of excipients.

2.7.2 New mathematical paradigm for LS system design

Spireas [2] developed a novel mathematical model to formulate LSCs with good flow and compressibility properties. The basic building blocks for creating this formulation are a suitable drug, a non-volatile solvent of choice with the highest solubility for the drug, a suitable carrier material with acceptable absorption, and a coating material with good adsorption properties. The new fundamental features of powder systems known as flowable liquid retention potential and compressible liquid retention potential of the powdered excipients included in the formulation serve as the foundation for this model.

The ϕ value can be explained as the extreme amount of liquid that can be held in unit volume of carrier material while still maintaining acceptable flow characteristics following admixing.

The ψ value can be explained as the extreme amount of liquid that can be held in unit volume of carrier material while still maintaining compression property following admixture [16].

The excipients ratio (R) or the ratio of carrier: coating material is given by the Eq. (2)

$$\mathrm{R}=\mathrm{Q}/\mathrm{q}$$E2

where,

R is ratio of carrier material to coating material, Q is carrier material and q is coating material.

For successful LS formulation design, the ratio R should be properly selected.

Liquid load factor (Lf) is defined as the ratio of amount of liquid medication to that of carrier in the LS powder system having acceptable appropriate properties and is given by the Eq. (3).

$$\mathrm{Lf}=\mathrm{W}/\mathrm{Q}$$E3

Where, W is the amount of liquid medication and Q is amount of carrier material.

The Lf value was calculated from the below Eq. (4).

$$\mathrm{Lf}=\mathrm{\varphi }\mathbf{+}\mathrm{\varphi }\left(1/\mathrm{R}\right)$$E4

Where, ϕ is flowable liquid retention potential value for carrier material and ϕ is flowable liquid retention potential value coating materials, respectively.

As a result, Lf value was initially derived using Eq. (4) for the purpose of developing LS system, using R value as a predetermined fixed value. Then, W can be calculated further as it is the weight of liquid medication (combined weight of drug and non-volatile solvent). Given that W and Lf values are known, Q (quantity of carrier) can be computed using Eq. (3). So, using the Eq. (2), it is possible to calculate the amount of q (amount of coating material) after knowing the values of Q and W.

2.7.3 Determination of angle of slide

The flowable nature of prepared LS powder can be assessed by specific parameter known as Angle of slide (θ). Powder flowability is considered an important factor as it plays a crucial role in pharmaceutical industries.

Uniformly prepared powder/solvent blends containing 10 grams of carrier or coating material with increasing amounts of solvent were prepared. Further, it is placed at one edge of metal plate containing smooth surface and tilted slowly till the admixture starts to slide. The angle of slide (θ) was defined as the angle produced between the plate and the horizontal surface. The angle matching to 33° is regarded as optimal flow behavior for LS powder system [17].

2.7.4 Flowable liquid retention potential determination

The Φ value indicating flowable liquid retention potential can be determined from the angle of slide (θ) values. To 10 grams of carrier or coating powder gradually increasing quantity of liquid vehicle was added; then mixed using a mortar and pestle to attain powder admixtures. On one end of a smooth polished metal plate, the powder-solvent admixtures were positioned individually. Later, the plate was gradually raised until it made an angle with the horizontal planet, at which point the mixture began to slide. This obtained angle (θ) gives the angle of slide [18].

Using Eq. (5), the flowable liquid retention potentials for each solvent-powder admixtures can be calculated

$$\mathrm{\Phi }\text{value}=\text{weight of liquid vehicle}/\text{weight of carrier or coating material}$$E5

2.7.5 Compressible liquid retention potential (Ψ value)

The Compressible liquid retention potential (Ψ value) for each solid powder excipient with solvent is carried out by gradually adding liquid vehicle to 1 gm powder material till uniform admixture is obtained. Then this admixture was compressed in the rotary tablet machine to prepare a tablet. The crushing strength value obtained between 5 and 7 Kgf was considered as an acceptable one. During compression, leakage of liquid medicament from the powder admixture must not be observed [2].

2.7.6 Load factor calculation (Lf)

The quantity of liquid retained by the carrier agent and coating agent depends on the excipient ratio (R) to maintain adequate flowable and compressible properties. As per the LS powder system preparation, the maximum amount of solvent retained within carrier material should not be exceed a limit. This characteristic amount of liquid is named as liquid Lf. The weight of the liquid medicine (W) divided by the weight of the carrier powder (Q) in an LS powder system yields the liquid load factor, or Lf.

$$\mathrm{Lf}=\mathrm{W}/\mathrm{Q}$$

Liquid load factor can be calculated by using Eq. (6) after determining Φ–values of carrier and coating agents.

$$\mathrm{Lf}\mathrm{\Phi }={\mathrm{\Phi }}_{\mathrm{CA}}+{\mathrm{\Phi }}_{\mathrm{CO}}\left(1/\mathrm{R}\right)$$E6

where, Φ_CA represents flowable liquid retention potential value for carrier agent and Φ_CO represents flowable liquid retention potential value for coating material.

R is the ratio of carrier (Q) weight to coating (q) weight present in the formulation. Eq. (6) is used to calculate load factor in LS formulations for obtaining acceptable flowability.

$$\mathrm{Lf}\Psi ={\mathrm{\Psi }}_{\mathrm{CA}}+{\mathrm{\Psi }}_{\mathrm{CO}}\left(1/\mathrm{R}\right)$$E7

Where, Ψ_CA and Ψ_CO represents compressible liquid retention potential values for carrier agent and coating agent respectively.

Eq. (7) is used to calculate load factor in LS formulations for obtaining acceptable compressibility [19].

Finally, suitable amounts of carrier and coating materials can be calculated using the above equations to produce acceptable flowing and compactible powders.

2.7.7 Preparation of drug loaded LSCs

LSCs were prepared according to the method described by Spireas and Bolton [2]. They were prepared by dispersing accurately weighed quantity of drug (50 mg) in non- volatile liquid vehicle showing maximum solubility for the drug. In a 20 mL glass beaker, a calculated quantity of drug equivalent to the dose is added to a calculated amount of vehicle and thoroughly mixed to generate liquid medication. Then a binary mixture was formulated comprising calculated amounts of carrier agent and coating agent; and continuously mixed for about 10 minutes in a mortar. The resulting liquid medication was mixed with binary mixture and blended in a porcelain mortar avoiding excessive trituration and particle size reduction.

The mixing process comprises of three stages as follows

1. Mixing the LS powder at a speed of 1 rotation/min for uniform distribution of liquid medication in powder blend containing carrier and coating material (binary mixture).

2. The LS powder should be applied in a homogeneous coating to the inner surface of mortar and left for 5 minutes to allow powder particles to absorb liquid medication.

3. Scrapping off LS powder off the surface of mortar using aluminum spatula.

Finally, super disintegrant was added to each batch and mixed for 30 sec, followed by addition of lubricant and mixed for 2 min. This resultant final LS powder formulation was compressed into LSCs using suitable punch in rotary tablet compression machine [20].

2.8 Characterization of drug loaded LSCs

The drug loaded LSCs are characterized in terms of both pre compression and post compression evaluation tests. The precompression evaluation tests include determination of powder flow properties for prepared LS powder systems. The flow properties of the LS powder system were characterized in terms of Tapped and Bulk density, Compressibility Index, Angle of repose and Hausner’s ratio.

2.8.1 Angle of repose (θ) (funnel method)

It is measured by fixed funnel method. The powder blend is passed through funnel until apex of powder pile touches tip of the funnel. A rough circle is drawn around the base of the pile. The angle of repose is measured using Eq. (8)

$$\mathrm{Tan}\left(\mathrm{\theta }\right)=\text{height of powder}\left(\mathrm{h}\right)\text{in}\mathrm{cm}/\text{radius of powder}\left(\mathrm{r}\right)\text{in}\mathrm{cm}$$E8

2.8.2 Bulk density

The bulk density is obtained by dividing mass of powder with its bulk volume. It was calculated using Eq. (9) in gm/ml.

$$\text{Bulk density}=\frac{\text{Weight of powder}}{\text{Bulk volume of powder}}$$E9

2.8.3 Tapped density

It is measured by taking accurately weighed 10 g of powder blend into a 100 ml graduated measuring cylinder. The initial volume was determined. The cylinder was initially tapped for 200 times from a distance of 14 ± 2 mm. The tapping process was again repeated additionally for 200 times. Finally, the tapped volume was noted [12]. The tapped density was calculated using Eq. (10) the following formula in gm/ml.

$$\text{Tapped density}=\frac{\text{Weight of powder}}{\text{Tapped volume}}$$E10

2.8.4 Carr’s index or compressibility index

Compressibility Index is calculated using Eq. (11) based on tapped and bulk densities which determines the ease of powder flow property.

$$\text{Compressibility index}\left(\%\right)=\frac{\text{Tapped Density}–\text{Bulk Density}}{\text{Tapped Density}}\times 100$$E11

2.8.5 Hausner’s ratio

The Hausner’s ratio is the proportion of a powder tapped density to its bulk density. It is calculated using Eq. (12).

$${\text{Hausner}}^{’}\mathrm{s}\text{ratio}=\text{Tapped density}/\text{Bulk density}$$E12

Powders with Hausner’s ratio 1 to 1.11, 1.12 to 1.18, 1.19 to 1.25, 1.26 to 1.34, 1.35 to 1.60 indicate free flowing, good, fair, passable, poor flow of powder respectively.

The post compression tests for the prepared LSC formulations were performed similar to that of tablets according to IP specifications [21].

2.8.6 Weight variation test

The weight of tablet is determined to ensure that tablet contains exact amount of drug. Around 20 LSCs from each formulation were selected randomly. They were weighed individually and the average weight was calculated using digital balance. The individual weights were then compared with that of average weight for each formulation batch. It is calculated using Eq. (13) the below formula,

$$\%\text{Deviation}=\frac{\left(\text{Individual weight of tablet}–\text{Average weight tablets}\right)}{\text{Average weight of tablets}}\times 100$$E13

2.8.7 Hardness

It is also termed as crushing strength of tablet. It is measured using Monsanto hardness tester and was expressed in kg/cm². The LSC whose hardness to be tested was placed between the spindle and anvil of Monsanto hardness tester. The screw knob is moved clockwise and then pressure is applied that holds the tablet in position. The scale is moved in order that the indicator is fixed at zero. The pressure is applied continuously until tablet breaks. The reading is noted, that indicates the pressure required to break the tablet. The test is performed thrice and the mean value was determined.

2.8.8 Friability

It is used to measure the mechanical strength of tablets. The friability of prepared LSCs can be determined using Roche friabilator (Mumbai, India). Around, 10 LSCs from each batch were weighed and placed in the chamber of friabilator. The chamber is rotated at speed of 25 rpm for a period of 4 min (100 rotations). At the end of test, the tablets were then dusted, re-weighed collectively and the percentage weight loss (friability) was calculated [22]. It is measured using Eq. (14)

$$\%\text{friability}=\frac{\text{Initial weight}-\text{final weight}}{\text{Initial weight}}\mathrm{x}100$$E14

2.8.9 Drug content uniformity

About 10 LSCs were randomly selected and crushed to powder in a mortar. The powder was weighed equivalent to unit dose of drug which was taken into 100 ml volumetric flask. Initially, 10 ml volume of methanol was added, followed by addition of buffer to make up final volume. The resulting solution was diluted, filtered and analyzed using spectrophotometer to determine the drug content [19].

2.8.10 Disintegration time

Disintegration time for LSC was performed by placing one tablet in each of the six tubes of the basket of USP Disintegration Tester (Electrolab, India) apparatus. Disc was placed above each tube and the apparatus was run using buffer solution as immersion medium. The apparatus is maintained at temperature of 37 ± 2°C. The assembly will be lifted up and down between 30 cycles/min. The time required for all the six tablets to disintegrate completely was noted as DT. The process is repeated thrice and the average disintegration time is determined [19].

2.8.11 In vitro drug release studies

The in vitro drug release profiles for LSCs were determined by means of Rotating Paddle, USP Type II dissolution test apparatus (Electrolab, Mumbai, India). The dissolution was performed in 900 ml of selected dissolution media (SGF or SIF) with paddle speed of 50 rpm. Aliquots of 5 ml samples were collected at predefined time intervals. To maintain constant volume and sink conditions, the dissolution medium was replaced with 5 ml of fresh medium. These samples were analyzed using UV–VIS spectrophotometer at λ_max of prepared drug. It is carried out in triplicates for each LSC batch and also compared with conventionally prepared directly compressed compacts containing an equivalent amount of drug for comparison [23].

2.9 Analysis of optimized LSCs

Based on the results of evaluation tests, one LSC formulation was optimized from the prepared batch and selected for further analytical characterization. This optimized drug loaded LSC was subjected to FTIR and DSC studies to determine presence of any possible interaction between drug and excipients. SEM studies were also performed to study surface morphology and XRD studies for determining the solid-state characterization.

2.9.1 Fourier-transform infrared spectroscopy (FTIR)

Drug-excipient interactions play crucial role in release of drug from the formulation and hence the compatibility studies were performed using FT-IR spectrophotometer. IR spectrum was determined for samples by FTIR-8400S spectrophotometer (Shimadzu, Japan) using KBr pellet method. In this method, 100 mg of dry KBr IR powder is carefully mixed with 5 mg of sample (drug or formulation). It is further compressed to transparent discs at a pressure of 12,000 psi under vacuum for about 3 min. The obtained disc was mounted in holder and the sample was scanned over a wave range of 4000 to 400 cm⁻¹, at a resolution of 4 cm⁻¹ using FTIR spectrophotometer. FTIR was executed for both the pure drug and LS powders [24].

2.9.2 Differential scanning calorimetry (DSC)

DSC Thermograms of pure drug and the optimized LSC formulation for drug were recorded using the calibrated Shimadzu DSC-60 (Shimadzu, Kyoto, Japan) [19]. Samples of weight around 3 to 5 mg were weighed. They were placed in aluminum pans whose lids were crimped taking Shimadzu crimper. The samples were investigated over a scanning rate of 10°C/min to determine their thermal behavior, covering a wide temperature range of 30–200°C under nitrogen atmosphere. The DSC was calibrated using indium standard [25].

2.9.3 Powder X-ray diffraction (PXRD)

The crystalline nature pure drug as well as samples can be determined by Philips Analytical XRD using copper target. At room temperature, the operating voltage was 40 kV and current used was around 55 mA [26].

2.9.4 Scanning electron microscopy (SEM)

The surface morphology characteristics of pure drug as well as the drug–carrier systems or formulations were assessed using scanning electron microscopy. The external surface morphology of the LSCs were studied using a scanning electron microscope (Hitachi TM 1000, Tokyo, Japan). The samples were first adhered to aluminum stubs, gold-coated sputter with double sided conductive tape of 12 mm diameter, and examined in the scanning microscope [27].

2.10 Stability studies

Stability can be explained as the extent to which a product will retain its specified limits throughout the shelf life. The accelerated stability studies for optimized LSC formulation were performed according to ICH guidelines at temperature of 40 ± 2°C and relative humidity (RH) of 75% RH ± 5% for duration of 6 months in a stability chamber. USP Type I flint vials are used to place the selected optimized formulations. They are then hermetically closed using bromo butyl rubber plugs and further sealed with aluminum caps. The samples were taken at specific time periods and evaluated for post compression tests. These results of aged samples were compared with fresh (initial) samples kept at room temperature and similarity factor was determined [28].

3. Conclusion

The purpose of the present study was to investigate the effect of liquisolid technique in improving the dissolution profile of poorly aqueous soluble drugs mostly that belong to BCS Class II and Class IV. In this investigation, preformulation study i.e. saturation solubility was performed for drug in order to determine extent of its solubility in liquid vehicle, which forms basis for preparation of LSCs. However, solvent showing highest solubility for drug was selected as liquid vehicle for preparing liquid medication.

Further, liquisolid systems were formulated by the technique described and patented by Spireas et al. The liquisolid compacts were formulated with addition of carrier material (such as Avicel PH102) and coating material (such as Cab-O-Sil M5). During formulations the chemical compatibility between drug and excipients was checked and confirmed by FTIR study. The liquisolid preparations were initially characterized by precompression study for flowability and compressibility. The liquisolid powder systems were compressed to obtain liquisolid compacts which were further characterized for post compression tests such as hardness, content uniformity, disintegration and dissolution profiles. The stability studies were also conducted and the tablet properties like hardness, drug content, disintegration and dissolution profiles were compared for freshly prepared and aged tablets.

The drug loaded liquisolid formulations showed higher drug release profiles when compared with the conventional dosage forms for the same drug. Hence, this technique proved a substitute method to develop solid oral dosage forms for poorly water-soluble drugs. The method uses appropriate excipient ratios of biodegradable polymers which not only improve drug release but also sustain the drug release characteristics of the water-soluble drugs. Finally, it can be concluded that LS technology was effective for enhancing the dissolution behavior as well as the bioavailability of poorly water soluble or practically water insoluble drugs in presence of non-volatile solvents. Thus, liquisolid approach has potential application for formulation research in improvement of dissolution rate and hence proved to be a promising tool as well an alternative technique to enhance the dissolution profiles of very low aqueous soluble drugs.

Abbreviations

BCS	biopharmaceutics classification system
LS	liquisolid
LSC	liquidolid compacts
PEG	polyethylene glycols
PG	propylene glycol
MCC	microcrystalline cellulose
HPC	hydroxypropyl cellulose
PVP	polyvinylpyrrolidone
HPMC	hydroxypropyl methyl cellulose
SSA	specific surface area
FM	fraction of molecularly dispersed drug
Sd	drug solubility
Cd	drug concentration