coating.pdf

Acta Poloniae Pharmaceutica Drug Research, Vol. 67 No. 1 pp. 312, 2010 ISSN 0001-6837Polish Pharmaceutical Society

Organic solvents are constantly present in thepharmaceutical production processes. The pharma-ceutical industry is one of the largest users of organ-ic solvents per amount of the final product (1). Theyare usually used at any step of the synthesis pathwayof an active substance or excipients, and sometimesduring the drug product formulation process.Because of some physical and chemical barriers,organic solvents cannot be completely eliminatedfrom the product by manufacturing practices, suchas drying in an elevated temperature underdecreased pressure or by lyophilization (freeze-dry-ing). Usually some small amounts of solvents mayremain in the final product. They are called residualsolvents (RS), also commonly known as organicvolatile impurities (OVI). Additionally, a drug prod-uct may also become contaminated by organic sol-vents from packaging, warehouse storage, or fromshipping and transportation.

For toxicological reasons manufacturers aspireto minimize the number and amount of solventsapplied in a drug production. Apart from the factthat they have no therapeutical value and may betoxic, they may additionally accelerate decomposi-tion of the product. Special directions published inpharmacopeias and ICH guidelines determine maxi-mum allowable amounts of RS in pharmaceuticalproducts (2-4). If amounts of RS are below the lim-its the analyzed product is cleared for sale.

In this article, many aspects of organic solventsuse in drug product development and manufacturingare presented (acceptable limits and regulations,synthesis, formulation, production, packaging, sol-vents removal, analytical methods) and new ideas oftheir replacement with the technologies used inother industries will be mentioned.

Regulations/legislationsGenerally, for objective reasons, the pharma-

ceutical industry is a tightly regulated branch ofmanufacturing. That is the reason why, based on thetoxicity of individual solvents, RS limits for phar-maceutical products and excipients have been set bydifferent associations.

In the past, the pharmaceutical industry neededto unify regulations and limits for residual solvents.For many years the United States Pharmacopoeiawas the only pharmacopoeia setting limits for resid-ual solvents in pharmaceutical products (chapter Organic Volatile Impurities). In 1990, limitsfor RS were proposed in Pharmeuropa (5) and, morerecently, in the second International Conference onHarmonization of Technical Requirements forRegistration of Pharmaceuticals for Human Use(ICH) guideline draft. In December 1997 the ICHpublished its Guidance for Industry Q3C whichbecame effective in March 1998. ICH guidelinecompromised regulatory authorities from Europe,

REVIEW

ORGANIC SOLVENTS IN THE PHARMACEUTICAL INDUSTRY

KATARZYNA GRODOWSKA1,2* and ANDRZEJ PARCZEWSKI1

1 Jagiellonian University, Faculty of Chemistry, Department of Analytical Chemistry, Ingardena 3, 30-060 Krakw, Poland

2 Pliva Krakw S.A., Mogilska 80, 31-546 Krakw, Poland

Abstract: Organic solvents are commonly used in the pharmaceutical industry as reaction media, in separationand purification of synthesis products and also for cleaning of equipment. This paper presents some aspects oforganic solvents utilization in an active pharmaceutical ingredient and a drug product manufacturing process.As residual solvents are not desirable substances in a final product, different methods for their removal may beused, provided they fulfill safety criteria. After the drying process, analyses need to be performed to check ifamounts of solvents used at any step of the production do not exceed acceptable limits (taken from ICHGuideline or from pharmacopoeias). Also new solvents like supercritical fluids or ionic liquids are developedto replace traditional organic solvents in the pharmaceutical production processes.

Keywords: organic solvents, residual solvents, acceptable limits

3

* Corresponding author: [email protected]

4 KATARZYNA GRODOWSKA and ANDRZEJ PARCZEWSKI

Japan and the United States, as well as representa-tives of the research based pharmaceutical industry.

According to Q3C guideline solvents are divid-ed into four groups (2). The first group (Class 1)contains known human carcinogens, compoundsstrongly suspected of being human carcinogens, andenvironmental hazards Table 1. These solventsshould be avoided, unless strongly justified. Thelimits for Class 1 solvents are listed as absolute partsper million in a material under testing (drug orexcipient). Class 2 solvents presented in Table 2ought to be limited because they are non-genotoxicanimal carcinogens or possible causative agents ofirreversible toxicity, such as neurotoxicity or terato-genicity. They are also suspected of other signifi-cant, reversible toxicities. Class 2 solvents limitsare listed in two ways (2). Option 1 uses the absoluteparts per million of solvents contained in the mate-rial being tested and is used in cases where the dailydose is known or fixed and is expressed by the for-mula:Concentration (ppm) = (1000 PDE)/dose (in grams per day) (2)

where: PDE permissible daily exposure limit inmilligrams.

In Option 2, the sum of amounts of residualsolvents present in each component of the drugproduct per day, should be less than given by PDE.The ICH Q3C guideline has illustrative tables show-ing a passing and failing Option 2 scenario. If a sam-ple fails Option 1, but passes Option 2 criteria, thenit passes the residual solvents requirement. If a sam-ple fails both Option 1 and Option 2 criteria then itfails the residual solvents requirement.

Class 3 solvents have permissions of dailyexposures of 50 mg (0.5%) or less (corresponding to5000 ppm or 0.5% under Option 1 described forClass 2) per day. Higher amounts may also beacceptable when the manufacturer proves that theamounts of Class 3 solvent is realistic with relationto manufacturing capability and good manufactur-ing practice. There is no solvent recognized as ahuman health hazard at levels normally accepted in

pharmaceuticals in this group. They are less toxic inacute or short-term studies, and negative in geno-toxicity studies.

There is also another group Class 4 solvents.For this group there is no adequate toxicologicaldata enabling formulation of acceptable limits. Ifmanufacturers want to use Class 4 solvents, theyshould supply justification for residual levels of thisclass solvents in a pharmaceutical product (2).

As with other guidelines, Q3C only addressesmarketed products and not materials used in clinicaltrials.

Organic solvents which are most commonlyused in the chemical industry are presented in Table 3.

Other reasons for control of residual solventsToxicity is the main and unquestionable reason

for control of residual solvent amounts, but some-times the presence of RS at levels well withinacceptable limits, could entail the risk of inducingphase transformations and jeopardizing the physico-chemical stability of an active substance, and final-ly the quality of the dosage form. A few reports onresidual solvents effects have appeared in literature,e.g. the effect of methylene chloride on the crys-tallinity of ampicillin trihydrate C16H19N3O4S3H2O)(8) and of residual ethanol on the phase transforma-tion of orthorhombic paracetamol (C8H9NO2) (9).Additional arguments for removing organic solventsfrom the drug product are the odor or the taste theycan cause, which are obviously not good drug attrib-utes, both for manufacturers and for patients.

Sources of residual solvents in a drug productIn a task of effectively removing or decreasing

the amount of organic solvents present in a drug prod-uct it is necessary to investigate ways the drug is con-taminated by the solvents. Therefore, a short descrip-tion of the main technological processes where organ-ic solvents are involved is presented below.

Before a pharmaceutical company obtains thefinal product tablets, capsules or other pharmaceu-

Table 1. Class 1 solvents (2)

Solvent Concentration

Concernlimit (ppm)

Benzene 2 Carcinogen

Carbon tetrachloride 4 Toxic and environmental hazard

1,2-Dichloroethane 5 Toxic

1,1-Dichloroethene 8 Toxic

1,1,1-Trichloroethane 1500 Environmental hazard

Organic solvents in the pharmaceutical industry 5

tical form, some elemental stages have to be per-formed: (a) synthesis of an Active PharmaceuticalIngredient (API), (b) production of a Drug Product(DP), (c) packaging.

At each of these stages the product can bepotentially contaminated with organic solvents. InFigure 1, different stages of the drug product manu-facturing process are presented. Stages marked withthicker frames are processes where organic solventsmay be in use or where a pharmaceutical substanceor product may become contaminated with organicsolvents (packaging). Sometimes the source andmeans of contamination determine the way ofremoving them or reducing their quantity. Forexample, if the solvent is occluded in crystals of an

API, recrystallization should be performed and if thesolvent is adsorbed on a surface of particles, a dry-ing procedure is recommended.

Synthesis of an Active Pharmaceutical Ingredient(API)

Effective synthesis of an API is, in most cases,a multilevel and complicated process. Generally,chemical synthesis consists of four steps: reaction,separation, purification and drying. During a synthe-sis process, a kind of solvent and its quality may bea critical parameter. Care must be taken for appro-priate solvent selection that may improve the reac-tion yield and influence product quality. Typical

Table 2. Class 2 solvents (2)

SolventPDE Concentration

(mg/day) limit (ppm)

Acetonitrile 4.1 410

Chlorobenzene 3.6 360

Chloroform 0.6 60

Cyclohexane 38.8 3880

1,2-Dichloroethene 18.7 1870

Dichloromethane 6.0 600

1,2-Dimethoxyethane 1.0 100

N,N-Dimethylacetamide 10.9 1090

N,N-Dimethylformamide 8.8 880

1,4-Dioxane 3.8 380

2-Ethoxyethanol 1.6 160

Ethylene glycol 6.2 620

Formamide 2.2 220

Hexane 2.9 290

Methanol 20.0 2000

2-Methoxyethanol 0.5 50

Methylbutylketone 0.5 50

Methylcyclohexane 11.8 1180

Nmethylpyrrolidone 48.4 4840

Nitromethane 0.5 50

Pyridine 2.0 200

Sulfolane 1.6 160

Tetralin 1.0 100

Toluene 8.9 890

1,1,2-Trichloroethylene 0.8 80

Xylene 21.7 2170


uses of solvents in the synthesis are solubilization(reaction medium), extraction and crystallization(purification). They may also take part in reactions,as reactants or catalysts and also take part inazeotropic or extractive distillations as entrainers.

The main function of solvents in a reaction stepis solubilization. As reaction media, solvents makesolutes more reactive by breaking cohesive forcesthat hold crystalline and liquid solutes together. Byalerting solvents, manipulation of reaction rate and,in consequence, product selectivity can be per-formed. That is why much research has been madeto understand and forecast the properties of solvents,which are important in all aspects of chemicalbehavior. Additionally, they can also be a part of asynthesis reaction, as reagents or catalysts.

An extraction process is the subsequent stageof API production, where a pharmaceutical sub-stance has a contact with organic solvents. In thisprocess synthesis products are separated from postreaction residues. Usually liquid-liquid separationsare carried between organic and inorganic fractions.A variety of solvents are used in extraction process,e.g. chlorinated solvents such as dichloromethane orchloroform as well as ketones, ethers, esters andalcohols. In extractions after a fermentation process,organic solvents, such as alcohols, toluene, acetone,acetates, or methylene chloride are utilized.

For the purification of an API, crystallizationprocess is used. In many crystallizations the control

of crystal properties, such as size and shape, is avery important factor, especially when the crystalmorphology determines the product quality like dis-solution rate or stability. Certain solutes, when crys-tallized from different classes of solvents, exhibitdifferent crystal size and morphology, carboxylicacids and ibuprofen are good examples (10).

When the crystallization is finished, solventshave to be removed. In the situation when they areabsorbed only on the surface of crystals, the dryingprocess can be applied. This stage is also a veryimportant process for the integrity of lattice. Defectspresent in crystals may favor subsequent polymorphicor pseudopolymorphic form of crystalline which maybe unstable (11). If the crystallization is led rapidly,solvents can remain inside the crystals. There aresome more or less complicated methods of removingthem effectively. One of them is recrystallization.

Regardless of the organic solvent function dur-ing API production, synthesis, purification and crys-tallization, the stages where organic solvents areused, are in general current.

FormulationFormulation is a process by which an API

compound is prepared in a form suitable for admin-istration. Drug product formulation is mostlydependent on the route of administration. From thispoint of view, drug products can be systemized asfollows (7):

Table 3. Solvents commonly used in chemical industry (6, 7)

Alcohols Ketones Halogenated solvents

Ethanol Ethylene bromideButanol Acetone Chloroform

2-Ethylhexanol Methyl ethyl ketone Ethylene chlorideIsobutanol Methyl isobutyl ketone Dichloromethane

Isopropanol Methyl isopropyl ketone TetrachloroethyleneMethanol Mesityl oxide Carbon tetrachloridePropanol Trichloroethylene

Propylene glycol

Amide Ethers Sulfur containing

1,4-DioxaneButyl etherEthyl etherDimethylformamide

Diisopropyl etherDimethyl sulfoxide

Tetrahydrofurantert-Butyl methyl ether

Amine Nitriles Esters

Pyridyne Acetonitrile Ethyl acetate

Aliphatic hydrocarbons Water Aromatic hydrocarbons

Cyclohexane TolueneHexane Xylene


oral route: solid dosage forms (tablets, capsules),syrups, oto-rhino-laryngology (ORL) route (nasal solu-tion, spray), local route (suppositories, transdermal systems,eye-drop formulation, spray), intravenous and intramuscular route (injectablesolutions, lyophilizate).

Some organic solvents can be used as a com-ponent of a final product and do not have to beremoved. Usually, they fulfill the function of dilu-ents or solubilizers, mainly in liquid and semisoliddrug forms when water cannot be used.

Into the group of liquid pharmaceuticals,creams/ointments, as well as medicines for swal-lowing and injecting, can be classified. Liquid pro-duction consists of dissolving the active pharmaceu-tical ingredient in an appropriate solvent, often withvarious preservatives and other additives, and mix-ing the ingredients completely (with the exceptionof suspensions, in which solid particles are sedi-mented). The most popular and the most desirablesolvent for all of these medicines is water. Thenewest technologies successfully avoid organic sol-vents in favor of water. However, sometimes the useof non-aqueous solvents is necessary. In such cases,they can be used individually or in mixtures of twoor more solvents (co-solvents). Usually, organic co-solvents improve solubility (solubilizers) or fulfillthe function of preservatives. Substances likeethanol, glycerol and glycols are applied as solubi-lizers (12). The presence of non-aqueous solvents ina drug form may positively influence API absorp-tion into the system.

Sprays, microemulsions and especially liquidsfor injections have to be prepared, stored and used insterile conditions. To prevent infection from micro-organisms, some quantities of germicides, fungi-cides and preservatives are added into solutions. Themost popular organic preservatives are ethanol in15-20% concentration, benzyl alcohol in 1% con-centration and phenol in 0.5% concentration.

During the formulation of tablets or capsules,which are classified in solid dosage forms, there arealso some stages where the product may have con-tact with organic solvents. One of these stages is thewet granulation technology.

In the wet granulation process, solvent (granu-lation fluid) causes massing of a dry mix powder.Solvents for granulation may be used alone or withaddition of other substances (binders or bindingagents) that improve the adhesive properties of par-ticles. In most cases water is used for the granulationprocess. However, sometimes water as a solvent can

strongly affect drugs stability because of long dryingtime (long exposure to heat) or when the product ismoisture sensitive (12). If water use has to beexcluded, solvents like ethanol, isopropanol, ace-tone or others can replace it.

It is very important that when organic solventsare used as granulation liquids to work with dryingequipment (tray or fluid bed dryers), which is explo-sion proof, all potential sources of sparks should beeliminated. The concentrations of organic vaporsand oxygen must be below explosion limits. In caseof the granulation with organic solvents it is gener-ally safer to use nitrogen as a process gas.

Besides granulate, also excipients can be apotential source of residual solvents. The raw mate-rials are generally manufactured to a much lowerpurity requirement than a drug substance (13).Hence, it is easy to understand why they can containa number of impurities including residual solvents.In this case, solvents toxicity and concentration lev-els should be monitored. Also interaction betweenexcipients and an API is possible and new impuritiesmay be created. Formic acid, its esters andformaldehyde are most commonly present in excip-ients as trace impurities. Even if formic acid (or itsesters) is present at low levels, it can interact withamino or hydroxyl groups from pharmaceuticalcompounds and form amides or esters.Formaldehyde in reaction with some amino groupscan form N-methyl derivative (14).

In tablets production, also during the film-coat-ing process organic solvents may be applied. It is acomplicated process and its scheme is presented inFigure 2. Typical coating ingredients are: polymers,plasticizers, pigments and wetting agents. In theearly 1970s the most popular wetting agents wereorganic solvents. Now, because of the environmen-tal and toxicological regulations, their usage isreduced and in most cases they are replaced withwater. However, certain types of film coatings andcoating processes require usage of organic solventslike methanol, ethanol, isopropanol, ethyl acetate,ethyl lactate, acetone, methylene chloride or 1,1,1-trichloroethane (15). In order to obtain a high-quali-ty tablet coating it should be dried immediately.From this point of view, organic solvents areunquestionably better than water because they evap-orate quicker. However, after drying some amountscan remain in a drug product.

PackagingPackaging, transportation, and storage can also

impact the level of residual solvents in the drugproduct. The quality of packing of pharmaceuticals


is a very important factor for the quality of the prod-uct. Final pharmaceutical drug products are pack-aged in many different types of containers such asplastic or glass bottles, foil blister packs, pouches orsachets, tubes and sterile vials. Mechanical equip-ment fills, caps, labels, cartons and packs the finalproducts in shipping containers. Drug packagingtypically contains a complex mixture of chemicalswhich could compromise the biological safety andefficacy of the drug.

In the case of liquid drug products, possibleinteractions between medium and packaging materi-al (especially polymeric materials like PCV-PVDC)should be checked. Also at this stage, drug productsmay have contact with organic solvents that can

remain in the packaging as residues from materialproduction. Accidental contamination during pack-aging, handling, or shipping should be managedthrough good handling and shipping practices as wellas appropriate monitoring of final product quality.

Removal of organic solventsIn the removal of undesirable organic solvents,

the drying process is involved. Different dryingtechniques are commonly used in the pharmaceuti-cal industry, such as: static bed drying (tray or truckovens), fluidized bed drying, moving bed drying(turbo bed dryers) or spray drying. Other, less popu-lar methods include dielectric (microwave) drying,tunnel drying and rotary current drying. Systems

Figure 1. Diagram of a selected manufacturing process in pharmaceutical industry


with vacuum, microwave or infrared drying havebecome more popular and sometimes their usagemay be necessary. It should be pointed out that thedrying process of substances containing organic sol-vents is dangerous and it is conducted under vacuumconditions (16). Usually a granulate, tablets or anactive substance are placed in one of several types ofdryers, then the dryer is sealed and a vacuum isapplied, the temperature is elevated and nitrogenflows through the dryer.

Some physical and chemical barriers that con-trol solvent removal are sometimes so strong thatadditional actions have to be performed to removeor reduce the amount of residual solvents. For thistask extraction with supercritical CO2 can be used.This technique is adapted to be used with polymericmicroparticles (17) and, unfortunately, is basicallylimited to slightly polar solvents.

Also, there are some special cases where resid-ual solvents are removed from therapeutic sub-stances in different ways. A good example of thiskind of procedure is radioactive holmium-166loaded poly(L-lactic) microspheres, prepared withthe use of chloroform by neutron irradiation in anuclear reactor. High energy radiation (neutron irra-diation or a gamma irradiation at a dose of 200 kGy)removes chloroform, which might have remained inthe microspheres. As a result of radiolysis, chloro-form is turned into chloride (18).

Control of residual solvents analytical methodologies

To assure the quality of drugs, residual sol-vents must be monitored carefully. Selective analyt-ical methods need to be developed. For this task,meaningful and reliable analytical data should begenerated at various steps of the new drug develop-ment (19). A variety of methods and analytical tech-niques are available for monitoring this kind ofimpurities. The primary criterion is the ability to dif-ferentiate between the compounds of interest. Otherimportant factors are sensitivity, simplicity of sam-ple preparation and time consumed by the analysis.

These requirements reduce the availability of meth-ods primarily to some separation methods. Also, insome cases thermal and spectroscopic techniquesmay be used. Only a brief review of analyticalmethods for RS testing is presented here and moreinformation on this topic will be described preciselyin the next paper.

Gas chromatography (GC) is a very usefultechnique for analysis of residual solvents. It canprovide the desired resolution, selectivity and quan-tification. Moreover, it is dedicated to volatile com-ponents and organic solvents in vast majority belongto this group of substances. Pharmacopoeias in theirgeneral chapters recommend GC coupled with head-space (HS) sampling system for qualitative andquantitative determinations of organic volatileimpurities (3, 4). Apart of HS-GC, other techniqueslike solid-phase microextraction (SPME) (20) orsingle drop microextraction (SDME) (21) can alsobe employed for residual solvents determinations.Flame ionization detector (FID) is usually used forthe detection of resolved compounds, but when theidentity of analytes need to be confirmed, massspectrometry (MS) can be coupled with GC. Alsoother specific or non-specific detectors e.g. electroncapture detector (ECD), photoionization detector(PID) or thermal conductivity detector (TCD) areused. In summary, gas chromatography in differentconfigurations (HS-GC, GC-MS, HS-GC-MS,SPME-GC, SDME-GC) is an excellent tool for thedetermination of volatile organic impurities.

When only Class 3 impurities are involved inthe active substance or raw materials and the drugproduct, then loss of weight method can be applied(3, 4). Other more sophisticated techniques like ther-mogravimetric analysis (TGA), differential thermalanalysis (DTA) or differential scanning calorimetry(DSC) are used as well. With the use of the above-mentioned methods only the sum of residual organ-ic solvents and water can be determined.

Various other techniques like infrared spec-troscopy (IR) (22) and nuclear magnetic resonance(NMR) (23, 24) have been applied to determine RS.

Figure. 2. Schematic presentation of film-coating process (15).


However, they can be effectively used only forselected solvents and usually detection limitsobtained are not satisfactory.

Ways of avoiding organic solventsMuch effort has been put to decrease the

amount of organic solvents involved in API synthe-sis and a drug product manufacturing. Pharma-ceutical companies constantly attempt to eliminatethe usage of organic solvents by following otherindustries, those that are more environmentallyfriendly. The manufacturers try to exchange moretoxic solvents to more friendly ones with similarproperties (like replacing benzene with toluene) orlook for some new innovations. Substances such aswater, supercritical fluids, fluorous phases, surfacesor interiors of clays, zeolites, silica gels, aluminaand ionic liquids are taken into consideration as apotential reaction media.

Supercritical fluids (SCFs)An example of those alternatives are supercrit-

ical fluids (SCF). The term supercritical fluid meansa substance above its critical point, at which thephase boundaries diminish. To exceed critical point,special temperature and pressure conditions need tobe obtained. Supercritical fluids have the mobilitysimilar to gases and dissolving properties, resem-bling liquid solvents which results in a high masstransfer, efficient penetration into porous matricesand high solvency. Their solubilizing power is sen-sitive to small changes in operating conditions, so itis possible to fine-tune the pressure and the temper-ature to adapt the solvent capacity of supercriticalfluids to a particular process (25).

Despite the fact that over the last two decadessignificant and effective progress has been made in theutilization of supercritical fluids, they are still notwidely used in the pharmaceutical industry. They canbe an ecological alternative to organic solvents,because they are neither restricted as residual solventsnor in the food or pharmaceutical industry. Nowadays,the most popular area of their use in this industry is forthe extraction of natural products like aromatic oils orcaffeine. Supercritical fluids can be useful as solventsin the production of some particular drugs, as well asin the extraction and separation of active pharmaceu-tical ingredients or particle size reduction. They offernovel solventless techniques, for the preparation ofdrug-loaded microspheres, compared to traditionalmicroencapsulation which use large amounts oforganic solvents. Moreover, SCF technology offersinnovative and economical methods to achieve sol-vent-free particulate delivery systems.

Although many SCF are suitable for pharma-ceutical applications, carbon dioxide is the mostwidely used because of its non-flammability, non-toxicity and low critical temperature (31C), whichis a very important feature in case of temperaturesensitive ingredients. Supercritical fluids have veryhigh solvation power or solute capacity at their crit-ical points, and additionally their solubility can bemodified by incorporating co-solvent or co-solute.Co-solvents are added to SCF in small quantities (1-5%) to receive required polarity and solventstrength. Methanol, ethanol, acetone or dimethylsulfoxide are typically used as co-solvents (26).

There are some supercritical fluid technologiesexploited in the pharmaceutical industry, like RapidExpansion of Supercritical Solutions (RESS), GasAntisolvent Recrystallization (GAS) or Solution-enhanced Dispersion by Supercritical Fluids, whichare being used to obtain increased quality of API orother substance particles size. As the result of thesetechnologies the smaller and the narrow sized parti-cles can be obtained. Also, in other stages of drugproduct formulation supercritical fluids may replaceorganic solvents. If so, why are they not commonlyused in the pharmaceutical industry?

The answer is connected with some limitations,which cause that SCF are not widespread in the pro-duction processes. Challenges, facing successfulimplementation of this new technologies in practice,include the lack of complete understanding of thefundamental principles involved, as well as the costsassociated with the specialized equipment neededfor required operating pressure and temperature.Sometimes it is hard to maintain accurate pressureand temperature conditions to achieve supercriticalstate for solvents. Another comes from the fact thatthere is no accurate and precise solubility databasefor the essential lab-scale model. The technology ofsupercritical fluids is still in development stage, andalso for this reason it is not commonly used in con-tinuous production (27).

Ionic liquids (ILs)Ionic liquids, often called green solvents, are

salts in which ions are poorly coordinated, whatresults that these salts are liquid below 100C or evenat room temperature (room temperature ionic liquids RTILs). It is possible to distinguish between themusing three criteria: the number of components in themelt, ion type organic or inorganic and acidbasecharacter of the ion. For one- and multi-componentinorganic ionic liquids almost every combination ofcation and anion is possible, which results in literal-ly thousands of melts. The situation is different for


organic ionic liquids, where the number of appliedorganic cations and anions is limited.

Ionic liquids, in general, exhibit low or evenimperceptible volatility, high solvency, wide liq-uidus range, thus their properties may be used inmany different ways, which are commonly regardedas the replacement of organic solvents in the chemi-cal and pharmaceutical industry. The pharmaceuticalindustry has cautiously studied their properties as analternative for solvents used in the synthesis of anAPI or in crystallization. There are hopes, that theirusage will make the synthesis process more efficientand thus lower the usage of raw materials. However,ionic liquids do not yet appear in a common use dueto the questions regarding purity, toxicity and regu-latory approval. Actually, it is still not known how todispose wastes which ionic liquids form and howthey affect air and water. The effect of contaminationof drug products with ionic liquids is also stillunknown. Moreover, manufactures can have prob-lems with getting approval from regulatory agencies(like FDA). This would probably be significant thateach process would require its own recycle, storageand recovery units (28). It is expected that theanswers to these questions and doubts will be foundsoon and the pharmaceutical industry will exchangeconventional organic solvents to the ones mentionedas alternatives or find an even better solution.

GMP and drug regulations in developing countries To be able to consistently control residual sol-

vents, the API and the drug product manufacturersmust apply GMP. Drug product manufacturers oftenbuy API from developing countries, like China orIndia, for economical reasons. Some problems withfulfilling GMP criteria may be encountered at APIproduction sites. In most countries API manufactur-ers are not inspected for compliance with GMP wellenough (29). The developing countries do not haveresources, or the capacity to regulate the API manu-facturers, drug regulations are rather weak and canprovoke circulation of nonefficacious or harmfuldrugs. Creating an effective drug regulatory mecha-nism in a developing country, is an expensive taskwhich requires professionals, appropriate legisla-tions and institution arrangements. Only then, thedeveloping countries may rely on the approval of theregulatory agencies in developed countries,designed to meet specific regulations (29).

CONCLUSIONS

There are many processes and activities duringmanufacturing of a drug product where organic sol-

vents are used in many different aspects.Sometimes, their usage improves product qualityand is a necessary factor. Good selection of a solventmay also be critical for a given process. However, inmost cases their presence in a final product is unde-sirable and manufacturers have to employ safe andeffective methods to remove them. New technolo-gies in polymers production, replaced organic sol-vents usage in a film-coating process almost entire-ly. Also, in a wetgranulation process, water isnowadays the most frequently used solvent and onlyduring more complex formulations, when the API issensitive to moisture or the process requires shorttime of drying, some organic solvents are involved.However, during an API synthesis, which is a com-plex process and requires different solvents, organicsolvents cannot be easily replaced by water. Evenwith the use of modern equipment for drying, someamounts of organic solvents can still remain in thefinal product. The acceptable limits for residual sol-vents are being published in pharmacopoeias and inICH Guideline and analytical methods need to besensitive enough for this task. Thanks to new tech-nologies in many cases the organic solvents can bereplaced by water, supercritical fluids, ionic liquidsor other innovations. Still it worth underlining thatthe aim of drug production is to provide the medi-cine with an effective therapeutic function and min-imize the acquirable risk for human health.

It can be concluded from the above presenta-tion that determination of trace organic solvents inpharmaceutical products appears as an importanttask, for which the relevant analytical methods willbe presented in the next paper.

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Received: 26. 01. 2009

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