Chapter 1 INTRODUCTION It has been well explained that solubility

Chapter 1
INTRODUCTION
It has been well explained that solubility, dissolution and gastrointestinal permeability are fundamental parameters that control rate and extent of drug absorption and its bioavailability 1. The water solubility of a drug is a fundamental property that plays an important role in the absorption of the drug after oral administration. The drug solubility is an equilibrium measure but also the dissolution rate at which the solid drug or drug from the dosage form passes into solution is critically important when the dissolution time is limited 2. Although the oral bioavailability of a drug depends on aqueous solubility, drug permeability, dissolution rate, first-pass metabolism and susceptibility to efflux mechanisms, aqueous solubility and drug permeability are also important parameters attributed to oral bioavailability 3. In drug discovery, the number of insoluble drug candidates has increased in recent years, with almost 70% of new drug candidates showing poor water solubility 4. For these drug candidates, poor aqueous solubility and poor dissolution in the GI fluids is a limiting factor to the in-vivo bioavailability after oral administration. Therefore, in-vitro dissolution has been recognized as an important element in drug development and thus increasing the dissolution rate of poorly soluble drugs and enhancing their bioavailability is an important challenge to pharmaceutical scientists 5, 6.

The encapsulation of liquids and semi-solids provides solutions for convenient delivery through improved oral absorption of poorly water-soluble drugs. In addition, low dose (content uniformity), highly potent (containment), low melting point drugs, those with a critical stability profile and those for which a delayed release is required are candidates for liquid or semi-solid formulations. Both hard and soft capsules can be considered and in each case the capsule wall may comprise gelatin or some other suitable polymer such as hypromellose. The choice of a hard or soft capsule will depend primarily on the components of the formulation which provides the best absorption characteristics as well as on the physical characteristics, such as the viscosity of the formulation and the temperature at which the product needs to be filled. The availability of new enhanced manufacturing equipment has brought new opportunities for liquid-filled hard capsules. Filling and sealing technologies for hard capsules, provides the formulator with the flexibility of developing formulations in-house from small scale, as required for Phase I studies, up to production.

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Liquid-fill hard gelatin capsule technology is becoming increasingly accepted by the pharmaceutical industry and while it can be hardly expected to replace more conventional dosage forms such as tablets and powder-filled capsules. Liquid-fill hard gelatin capsule technology was established in the early 1980s as an alternative to soft gelatin capsules and offered a number of specific Advantages such as lower moisture and gas transmission, use of high melting point excipients, plasticizer and preservative-free, lower moisture content, ease of coating, and choice of capsule composition7.

Liquid fills
Liquid fills can deliver active pharmaceutical ingredients (APIs) that are otherwise difficult or impossible to deliver via other solid dosage form. That has led many research and development scientist to reappraise their library of compound to identify promising substances. If any were rejected solely because their poor stability and bioavailability posed formulation challenges, then liquid delivery could offer a solution because it would improve bioavailability and adsorption. It’s even better if the API exist in liquid form because then it’s already solubilized and readily dispersible. In that state, even a poorly soluble API could be absorbed.

The liquid forms also provide a stable environment for liable actives and protects against oxidation. Liquids also promote fill weight uniformity, efficacy, stability, and safety, especially when the API is highly potent or toxic. Liquid fill can also reduce development time because they are typically a mixture of only one or two excipients. As a result, less time is spent on development and scale-up because fewer experiment replicates are required.

On the business side, liquid fill can lengthen product lifecycles and protection because they enable you to reformulate old products and re-introduce them in a new form. That creates exclusivity and protects your market share.

Liquid filled hard gelatin capsule
The hard gelatin capsule has been conventionally used as a dosage form for Rx and OTC drugs and herbal products, which are formulated either as powder or pellets. Various categories of drugs, however, demand new and different ways of formulation and the market demands that these products are developed and launched in an ever decreasing time period.

Liquid filled hard gelatin capsule is well established as a solid dosage form for convenient administration of drugs orally in a liquid form. Liquid filled capsule technology can be used for liquid and semisolid fills in two-piece gelatin or HPMC capsule with or without banding. This range of liquid composition available to accommodate even the most challenging drug compounds in capsules has increased significantly in recent years. In particular, it is possible to solubilize many drug compounds in a microemulsion pre-concentrate inside the hard gelatin capsules such that on subsequent dispersion in the gastrointestinal tract, the drug remains in solution. It is considered that this technology can make a significant contribution to the development of efficacious pharmaceutical products by providing the flexibility to rapidly develop and test in-house formulation when only small quantities of drug substance are available.

This unique, flexible and elegant dosage form has a proven track record for addressing complex formulation challenges and improving or re-positioning existing formulations. LFHC provides secure protection to drug compounds in terms of leak-proof, airtight encapsulation that is impermeable to moisture, oxygen and light.

Liquid filling hard gelatin capsules have gained exposure for their ability to increase solubility and bioavailability of poorly aqueous soluble drugs. In drug discovery, about 40% of new drug candidates display low solubility in water, which leads to poor bioavailability. Increasing the aqueous solubility of insoluble and slightly soluble drugs is major importance because most of the newly developed drugs are highly lipophilic in nature and its analysis is mainly carried out using organic solvents like methanol, chloroform, ethanol, benzene, acetone, toluene, carbon tetrachloride, diethyl ether, and acetonitrile. Most of these organic solvents are toxic, volatile, and costlier 8.

1. Drug categories suitable for filling into capsules:
1.1 Drugs with Poor bioavailability
Reports say that the bioavailability of the poorly water-soluble drugs can be significantly enhanced when formulated as a liquid in a soft gelatin capsule 9-12.

1.2 Drugs with a Low melting point:
Materials which have low melting points or are liquid at room temperature present difficulties when formulating as dry powders, often requiring high concentrations of excipient to avoid processing problems13-16.

1.3 Potent drugs:
Drugs in this category present two main challenges; how to achieve acceptable content uniformity and how to control cross-contamination and worker protection 17-19.

1.4 Sustained release drug candidates:
By choosing an appropriate excipient the release rate of an active ingredient can be modified. E.g. Soybean oil and glyceryl monostearate 20-23.

1.5 Critical stability
Sensitivity to moisture is an aspect of formulation which can be minimized by incorporating the drug into either a hydrophilic or lipophilic matrix. For example, the antibiotic vancomycin hydrochloride is highly hygroscopic and to achieve acceptable stability it needed to be formulated as a lyophilized powder for reconstitution 24.

Table 1. Some products marketed as liquid-filled hard gelatin capsules
API characteristic API Trade name/company
Poorly soluble Nifedipine
Ibuprofen
Piroxicam
FenofibrateFenogal
Danthron
Cyclosporin A Aprical®/RentschlerSolufen®/SMB
Solicam®/SMB
Fenogal®/SMB
Co-Danthramer®/
Napp
Gengraf®/Abbott
Low melting point Oils of avocado and soya
Ethosuximide
Peppermint oil
Saw palmetto
Essential phospholipids Piascledine®/
Pharmascience
Suxilep®/Jenapharm
Colpermin®/Tillotts
Permixon®/Pierre
Fabre
Lipostabil®/Aventis
Critical stability Vancomycin hydrochloride Vancocin®/Lilly
Short half-life requiring
frequent dosing Captopril Captoril®/Sankyo
Advantages of hard gelatin capsules over soft gelatin capsules Encapsulation
Table 2. Advantages of hard gelatin capsules over soft gelatin capsules
Hard gelatin capsule Soft gelatin capsule
Contain 4-5 times less gelatin than soft gelatin capsules. Require 4-5 times more gelatin than the hard gelatin capsules.

Require no other additives consist of water and gelatin only. Require addition of glycerine for softening purpose.

Allow step-by-step filling of 2 different formulations (i.e. 2-stage release) Have to be sealed immediately after filling one substance (filling and sealing are one and the same process.
Heat resistant: Allow filling of thermo-stable substances up to 75 0c Filling temperature limited to about 35 0c: Filling of solid substances with higher melting point impossible.

Are stable in hot climates. Tend to stick together and become gluey.

Will disintegrate faster due to the capsule wall being five times thinner than the walls of soft gelatin capsules. Will disintegrates slower due to the thickness of its gelatin/glycerin wall.

Less product migration into the shell, less diffusion of odors. Glycerine acts as a plasticizer by disrupting the gelatin structure consequently, higher diffusion into and through the walls.

Constant external dimensions (easier blistering /packaging) Dimensions vary according to filling weight and vary throughout a batch.

2. Suitability of fill materials
As the tendency for poorly water-soluble drugs to enter the pipeline increases so does the challenge to find innovative ways of developing bioavailable and stable dosage forms. Excipient suppliers, encouraged by the potential opportunities in this field, are developing new materials comprising mixtures of functional excipients.

The area of contact between the capsule shell and a liquid fill material is greater than is the case with a powder-filled capsule. The potential for interactions must, therefore, be checked.

2.1. Moisture exchange fill-shell
A hard gelatin capsule contains 14-16% moisture, which acts as a plasticizer for gelatin. A hygroscopic material, when filled into the capsule, could extract moisture from the shell thereby inducing embrittlement. The potential for this is checked by storing capsules filled with the product under various conditions of relative humidity from 2.5 to 65% 26.

The acceptance criteria have been set at a change in weight of plus or minus 2%.

2.2. Mechanical properties
The change in capsule brittleness with relative humidity study follows the monitoring of the mechanical properties of capsules stored at various relative humidities and is of critical importance in determining compatibility between the fill material and the capsule shell. Acceptance criteria proposed are that significant capsule brittleness should not be detected in capsules stored at 30% and 50% relative humidity for four weeks.

2.3. Recommended Properties (Temperature And Viscosity) of Fill Materials
The important factors to bear in mind during a liquid filling operation are temperature and viscosity of fill material and in the case of a suspension the particle size of the suspended drug. Whereas in principle any excipient found to be compatible with the gelatin shell can be used, in practice in a manufacturing environment the viscosity of the fill material is important. If the viscosity is too low splashing of the bushings may occur which could contaminate the area of overlap between the capsule body and cap and prevent a good seal from being formed.
The absence of a clean break during dosing (“stringing”) can have the same effect. The guidelines for problem free filling are given in Table 3.

Table 3. Recommended guidelines for dosing liquids/semi-solids into hard gelatin capsules
Parameter Recommendation
Temperature of fill material Max. ~ 70°C
Viscosity at the temperature of the dosing 0.1 – 1 Pa s
Visco properties A clean break from dosing nozzle
The absence of “stringing”
The particle size of suspended drug < 50 ?m
2.4. Excipients compatible with hard gelatin capsules
Excipients which, from the aspect of compatibility, can be considered to be suitable for formulation of drugs into hard gelatin capsules, are shown in Tables. They have been classified into three arbitrary groups:
• Lipophilic liquid vehicles
• Semi-solid lipophilic vehicles/viscosity modifiers for lipophilic liquid vehicles
• Solubilizing agents, surfactants, emulsifying agents and adsorption enhancers
Table 4. Excipients for Liquid Filled Hard Gelatin Capsules
Lipophilic
liquid vehicles Refined especially oils Arachis oil, Castor oil, Cottonseed oil, Olive oil, Soyabean oil, Sesame oil, Maize(corn)oil and sunflower oil
Medium chain
Triglycerides Akomed R (Caprylic/capric triglycerides)
Miglyol 810 (lactic acid/capric triglyceride)
Miglyol829 (succinic triglyceride)
Miglyol840(propanediol dioctanoate/dicaprate)
Softisan645 (bis polyacyladipic diglyceride1)
Lauroglycol FCC (Propylene Glycol Laurate), Captex 355
Semisolid
lipophilic
vehicles Hydrogenated oils Arachis oil (Groundnut 36), Castor oil (Cutina HR), Cottonseed oil (Sterotex) and Palm oil (Softisan 154)
Waxes Cetosteryl alcohol, Cetyl alcohol and Steryl alcohol
Gelucires Gelucires 33/01, 39/01, 43/01
Solubilizing
agents,
surfactants,
emulsifying
agents Emulsifiers-
W/O emulsifier,
O/W emulsifier Imwitor 780K(Isostearyl Diglyceryl Succinate)
Imwitor380 (Glyceryl Cocoate/Citrate/Lactate)
Surfactants Tween 80, Poloxamer 124 and poloxamer 188
Liquid solubilizer Plurol Oleique CC497 (Polyglyceryl Oleate)
Fatty acid esters Softigen 701(Glyceryl Ricinoleate)
Softigen767(PEG-6Caprylic/Capric Glycerides)
Polyethylene Glycols PEG>4000
Gelucires Gelucire 44/14, 50/13
Key Considerations in Capsule Filling
Capsule filling is a complex process, and the product to be encapsulated must be well developed to ensure mass uniformity. It is possible to fill powders, granules, non-aqueous liquids, non-aqueous gels, and thermo-setting formulations into capsules. For solids, powders with poor flow properties can be problematic because of poor fill weight control. Liquids with very low viscosity can leak from two-piece shells soon after filling. Hygroscopic liquids can cause embrittlement in capsule shells.

When designing the formulation, it is essential to consider the physical properties of the fill mass required (e.g. viscosity) for the capsule filling process and to ensure the chemical and physical stability of the final dosage form. It is therefore critical to foresee potential interactions between the fill mass and the capsule shell material, as these can lead to problems during manufacturing and for their long-term stability. One of the key factors to consider is the extent of water exchange between the formulation and the capsule shell. The hygroscopic and hydrophilic components in the fill mass can lead to unacceptable shell changes in hard gelatin capsules, e.g. brittleness or softening.

Capsule size and fill weight
The choice of capsule size and fill weight is dictated by the unit dose requirements and the formulation to be used. In principle, any type of formulation may be dosed into hard capsules, from blends or granules, to coated pellets, to other oral dosage forms such as tablets, micro-tablets, smaller capsules, including various combinations of any of the mentioned forms. It is also possible to fill liquids, provided that the material of the capsule (generally gelatin, although there are other alternatives) is not soluble in the solvent used in the formulation.

Due to the need for a plasticizer in the capsule shell formulation, conventional hard gelatin capsules have high water content (13-16%). For this reason, hygroscopic products can absorb moisture from the capsule, causing the capsules to become brittle, which can break under mechanical stress. On the other hand, such transfer of moisture to the contents of the capsule could generate problems of physical stability (crystalline form) or chemical stability of the API.

To solve these problems, capsules with low moisture content can be developed, either by using plasticizers other than water or other polymers, such as hydroxypropyl methylcellulose (HPMC), which is the most widespread alternative.

Finally, mixtures with materials containing reactive aldehydes are not suitable for capsule filling, as they favor the “cross-linking” effect experienced by the gelatin, reducing the capsule’s solubility. Once the formula of the contents of the capsule is developed and the weight to be dosed is known, it is easy to define the most appropriate capsule size. The body of each size of capsule has a defined volume; and by knowing the density of the mixture to fill, we can establish the volume that will occupy the weight that must be filled in each capsule. All capsule suppliers provide capsule size tables that facilitate the choice of capsule size.

Table 5: Capsule dimensions and filling capacities
Size Outer Diameter (mm) Height or Locked Length (mm) Actual Volume (mL)
000 9.91 26.14 1.37
00 8.53 23.30 0.95
0 7.65 21.70 0.68
1 6.91 19.40 0.50
2 6.35 18.00 0.37
3 5.82 15.90 0.30
Physical characteristics of fill formulations
Fill formulations for hard gelatin capsules may be Newtonian liquids, such as oils, thixotropic or shear thinning gels or semi-solid matrix products that are filled at elevated temperatures and in which the API is either dissolved or suspended as a fine dispersion.

In principle any formulation composition found to be compatible with gelatin can be used provided that the viscosity of the fill material conforms to the requirements of the filling process. In addition, fill formulations should not show stringing and should allow for a clean break from the dosing nozzle. Final modifications to the flow characteristics of the formulation may need to be made after trials on the specific machine and dispensing pump which will be used for filling the capsules.

Challenges in capsule filling
Viscosity
For liquid formulations, very low viscosity liquids should be avoided due to the potential for leakage.

Solvent
The main challenge when filling liquids in hard gelatin capsules is to find the right solvent (i.e., one that does not interact with the capsule material).
Compatibility of Fill Materials
The properties of the API dictate whether it is a good candidate for liquid filling. Next, suitable excipients are evaluated, with an understanding that neither the API nor the excipients should cause the gelatin shell to gain or lose excessive moisture, which can cause the shell to lose its mechanical strength. All substances must also be chemically compatible with gelatin 24. To maintain flexibility, the capsule shell must retain a moisture content of 13-16%. Below that range capsules become brittle and measure the moisture exchange between the fill material and the shell, fill the capsules with the product in question and store them at different levels of relative humidity (RH) (i.e., 2 period, the water exchange across the range of RHs should not exceed ±2%.
Fill materials that exchange more than ±2% moisture compared to empty shells stored under the same conditions are not suitable for liquid filling. The capsule’s mechanical resistance must be checked in relation to moisture content. This involves storing the filled capsules for 1week at different RHs and then testing them for resistance to breakage and deformation. Chemical compatibility the fill material causes the protein chains of the gelatin to cross method of monitoring cross-linking is to first store the fill material inside the hard gelatin capsules under ICH accelerated storage conditions (40°C at 75% RH), and then replace the fill material with acetaminophen. Next, conduct a dissolution test according to USP guidelines to compare the dissolution profiles of the filled and unfilled capsules stored at the accelerated conditions. Lipophilic liquid vehicles, Semisolid lipophilic vehicles, solubilizing agents, surfactants and emulsifying agents that are compatible with hard gelatin capsules are listed in table 2 25.

Liquids are an essential part of the capsule content. Only those liquids that are both water miscible and volatile cannot be included as major constituents of the capsule content since they can migrate into the hydrophilic gelatin shell and volatilize from its surface. Water, ethyl alcohol and emulsions fall into this category.

There are a large number of liquids that do not fall into the above category and thus can function as active ingredients, solvents or vehicles for suspension type formulations. These liquids include aromatic and aliphatic hydrocarbons, high molecular weight alcohols, esters or organic acids. The most widely used liquids for human use are oily active ingredients such as vegetable oils(soybean oil), mineral oil, non-ionic surface active agents(polysorbate 80) and PEG (400 and 600) either alone or in combination.

Solids that are not sufficiently soluble in liquids or in combinations of liquids are capsulated as suspensions. Most organic and inorganic solids or compounds may be capsulated. Such materials must be 80 mesh or finer in particle size, owing to certain close tolerances of the capsulation equipment and for the maximum homogeneity of the suspension. Many compounds cannot be capsulated, owing to their solubility in water and thus their ability to affect the gelatin shell, unless they are minor constituents of a formula or are combined with a type of carrier (liquid or solid) that reduces their effect on the shell. Examples of such solids are strong acids (citric), strong alkalies (sodium salts of weak acids), salts of strong acids and bases (sodium chloride) and ammonium salts. Also, any substance that is unstable in the presence of moisture (eg. Aspirin) would not exhibit satisfactory chemical stability in soft gelatin capsules.

A brief description of sealing methods:
Once closed, the capsule must be sealed to prevent leaks and tampering. A hydro-alcoholic fusion process (described in the USP’s capsule monograph) is one method of sealing 26. This fusion process begins with an application of less than 50?l of sealing solution to the cap-body interface. The solution penetrates the overlapping cap and body by capillary action, while a vacuum removes any excess sealing fluid from the capsule. Next, gentle application of warm (40-60°C) air fuses the gelatin of the cap and body together and evaporates the sealing solution. The entire process takes less than 1 minute and transforms the two-piece hard capsule into a leak-free dosage unit. Once sealed, the capsule meets tamper-evidence guidelines since it cannot be opened without visibly altering it.

Table 6. Stages of the hard gelatin capsule sealing process
Stage Process
1. Moisturizing 50:50 water/ethanol mixture sprayed onto join and capillary action draws liquid into the
space between body and cap. Excess fluid removed by suction. Melting point of gelatin
lowered by presence of water.

2. Warming Application of gentle heat of approx. 45°C completes the melting over a period of about one minute and the two gelatin layers are fused together to form a complete 360° seal.

3. Setting Gelatin setting or hardening process is completed while the product returns to room temperature. This process is best carried out on trays
Capsule stability:
Unprotected soft capsules (i.e., capsules that can breathe) rapidly reach equilibrium with the atmospheric conditions under which they are stored. This inherent characteristic warrants a brief discussion of the effects of temperature and humidity on these products, and points to the necessity of proper storage and packaging conditions and to the necessity of choosing an appropriate retail package. The variety of materials capsulated, which may have an effect on the gelatin shell, together with the many gelatin formulations that can be used, makes it imperative that physical standards are established for each product.

Refrence
1 Amidon GL, Lennernas H, Shah VP, et al. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res 1995;12:413e420.

2 Williams HD, Trevaskis NL, Charman SA, et al. Strategies to address low drug solubility in discovery and development. Pharmacol Rev 2013;65:315e499.

3 Krishnaiah YSR. Pharmaceutical technologies for enhancing oral bioavailability of poorly soluble drugs. J Bioequiv Bioavailab 2010;2:28e36.

4 Kawabata Y, Wada K, Nakatani M, et al. Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications. Int J Pharm 2011;420:1e10.

5 Hu J, Johnston KP, Williams RO. Nanoparticle engineering processes for enhancing the dissolution rates of poorly water soluble drugs. Drug Dev Ind Pharm 2004;30:233e245.

6 Costa P, Sousa Lobo JM. Modeling and comparison of dissolution profiles. Eur J Pharm Sci 2001;13:123e133.

7 Singh D. A review on self-emulsifying drug delivery system: Promising approach to enhance bioavailability. J Drug Discov Ther 2014;2.

8 Cole ET. Challenges and opportunities in the encapsulation of liquid and semi-solid formulations into capsules for oral administration. Capsugel; 2007.

9 Bhawna Bhatt S.S. Agrawal Capsules Pharmaceutical Technology, 2007, 1-26
10 Bhavisha Rabadiya, Paresh Rabadiya, Ijprbs, 2013, 2(3): 42-71.

11 Ghirardi P, Catenazzo G, Mantero O, Merotti GC and Marzo C. J. Pharm. Sci., 1977, 66(2): 267-269.Cuine A et al., Pharm. Ind.,1987, 40(6): 654-657.

12 Walker SE et al., J. Pharm. Pharmacol., 1980, 32: 389-393.

13 Walker SE, K. Bedford, and T. Eaves, British patent, 1980, 30: 572-226.

14 Duerr M, Fridolin HU and Gneuss KD, Acta Pharm. Technol., 1983, 29 (3): 245-251.

15C. McTaggart et al., J. Pharm. Pharmacol., 1984, 36: 119-121.

16 Doelker C et al., Drug Dev. Ind. Pharm.,1986, 12 (10): 1553-1565.

17 Lahr W, Pharm. Ztg., 1986, 131(15): 871-874.

18Lipinski CA, Kobe, 1999, 19-21.

19 Robinson JR, Bulletin Technique Gattefosse, 1996.

20 Kovarik JM, Mueller EA, Van JB, Tetzloff W and Kutz K, J. Pharm. Sci., 1994, 83: 444-446.

21 Patent, Oil-Free Pharmaceutical compositions containing cyclosporin A, WO 93/20833, 1993.

22 Hawley AR, Rowley G, Lough WJ, Chatham SM, Drug Devel. Ind. Pharm., 1992, 18 (16): 1719.

23 Howard JR and Gould PL, Drug Dev. Ind. Pharm., 1987, 13 (6): 1031-1045.

24 Seta Y et al., Int. J. Pharm., 1988, 41: 263-269.

25 W. J. Bowtle, N.J. Barker, and J. Wodhams. “A New Approach to Vancomycin Formulation Using Filling Technology for Semisolid Matrix Capsules.” Pharm. Technol. 12 (6): 86-97 (1988).

26 D. Cadé and N. Madit, “Liquid Filling in Hard Gelatin Capsules – Preliminary Steps”, Bulletin Technique Gattefossé, 1996.

28 Cade and Madit, Capsugel Library, BAS 191.

27 Vijaykumar N, Anusha Reddy R, Journal of Pharmacy, 2013, 1(1) 10-18.

27 Licaps, Capsugel, Greenwood, SC. Sven S, Capsugel B. Hard gelatin capsules today and tomorrow. 2 edn.Capsugel Library Greenwood, USA, 2002: pp. 3-23.

28 Liquid Encapsulation Microspray Sealing (LEMS), Capsugel, Greenwood, SC. Wittwer F, Pharm. Manuf.,1985, 2: 24-27.

30 Cade D, Cole ET, Mayer and Wittwer F. Acta Pharm. Technol., 1987, 33(2): 97-100.

31 Remington – The Science and Practice of Pharmacy, 20th Edition, Volume – 1).