*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 nonaqueous 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)

$$\mathbf{R} = \mathbf{Q}/\mathbf{q} \tag{2}$$

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).

$$\mathbf{L}\mathbf{f} = \mathbf{W}/\mathbf{Q} \tag{3}$$

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).

$$\mathbf{L}\mathbf{f} = \boldsymbol{\Phi} + \boldsymbol{\Phi}(\mathbf{1}/\mathbf{R}) \tag{4}$$

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

*Development of Liquisolid Compacts: An Approach for Dissolution Enhancement of Poorly… DOI: http://dx.doi.org/10.5772/intechopen.108706*

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

Φ value ¼ weight of liquid vehicle*=*weight of carrier or coating material (5)

#### *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.

$$\mathbf{L}\mathbf{f} = \mathbf{W}/\mathbf{Q}$$

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

$$\text{Lf } \Phi = \Phi\_{\text{CA}} + \Phi\_{\text{CO}}(\mathbf{1}/\mathbf{R}) \tag{6}$$

where, ΦCA represents flowable liquid retention potential value for carrier agent and ΦCO 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.

$$\mathbf{L}\mathbf{f}\,\Psi = \Psi\_{\mathbf{CA}} + \Psi\_{\mathbf{CO}}(\mathbf{1}/\mathbf{R})\tag{7}$$

Where, ΨCA and ΨCO 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


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)

$$\text{Tan}\left(\theta\right) = \text{height of powder (h) in cm/radius of powder (r) in cm} \tag{8}$$

#### *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.

$$\text{Bulk density} = \frac{\text{Weight of power}}{\text{Bulk volume of power}} \tag{9}$$
