Wypych Handbook of Solvents

14.21.1.2.1.5 Solvents used for extraction and preparative chromatography

As in the precedent cases they have to be absolutely inert (as far as it is possible) and with a high degree of purity for the reasons already evoked. In case of preparative chromatography a special care will be taken concerning the chemical inertia to adsorbate9 of the solvents constituting the mobile phase and the fact that impurities or additives contained in the solvents in a way not under control could impair significantly the reproducibility of the retention times.

14.21.1.2.1.6 Nature and origin of impurities contained in solvents10

It should be reminded here that a solvent used at the industrial level is rarely pure (we mean here no impurity analytically detectable).

Industrial solvents may contain:

•impurities coming from their origin or their manufacturing process

•impurities originating from the container during transportation

•stabilizers

•denaturing agents

•impurities resulting from a transformation of the solvent during the chemical

reaction

These impurities or side products should be look for as far as it is possible when assessing the purity of the solvent. In fact they could be less volatile than the main solvent and could finally concentrate in the pharmaceutical product.

We will now review shortly the nature of all these kinds of impurities of the most often used solvents.

14.21.1.2.1.6.1Impurities coming from the origin or the manufacturing process of the solvent1,10

Table 14.21.1.2. Solvent impurities

Ethanol

Aldehydes, ketones, esters, water, ethyl ether, benzene (if anhydrous ethanol)

N.B.: Some alcohols obtained by fermentation could contain pesticides. It is necessary to obtain from the purchaser some guaranty in requiring limit contents (expressed in Parathion e.g.).

Aliphatic ethers/cyclic ethers

14.21.1.2.1.6.2 Impurities originating from the container during transportation

It relates to contamination coming from tankers or drums not correctly cleaned. These concerns of course solvents of low quality conveyed in industrial quantity. In case of utilization of such solvents, the user has to bear in mind that some incidents or uncommon behavior may find an explanation based on this considerations.

14.21.1.2.1.6.3 Stabilizers

It is of course very difficult to know every stabilizer used. There is here an important problem of confidentiality. We quote thereafter some of them which are well known.

14.21.1.2.1.6.4 Denaturing agents

This process is relevant primarily to ethanol. Common denaturing agents are: methanol, isopropanol, ethyl acetate, toluene.

14.21.1.2.1.6.5 Transformation of the solvent during the chemical reaction

Solvents are rarely chemically inert. During the reactions where solvents are involved, they can undergo chemical transformation generating impurities which can be found, for example in the DS.

This is a huge field which cannot be exhaustively covered. We give below a few examples of well-known side reactions.

• Acetone in acidic media is easily transformed into mesityl oxide:

So do not forget to test for it when performing residual solvents analysis on drugs.

•In basic medium the diketone-alcohol is obtained:

•DMF can be hydrolyzed in presence of hydrochloric acid:

•Acids undergoing reaction in alcoholic media can be partially transformed into esters

•Transesterification reaction. Take care when, for example, recrystallization has to be performed for a molecule containing an ester group:

•Aldehydes (even ketones) can be transformed in alcoholic solutions into ketals:

• From time to time the solvent can react in lieu of the reagent.

In a synthesis aimed to prepare 3-chloro-1-methoxy-2-propan-2-ol starting from chloromethyloxirane and methanol, traces of ethanol present in methanol gave the corresponding ethoxylated compound:

Another and final example concerns the preparation of a urea derivative using the reaction of an amine and isocyanate in presence of isopropanol:

Other examples could be found. These obvious examples stress the need for close collaboration between chemists and analysts when elaborating chemical syntheses and corresponding quality control monographs.

14.21.1.2.2 Drug products11,12

14.21.1.2.2.1 General points

Because ultimately it is the DP which is administered to the patient, it is necessary to have the quality of the solvents potentially used in the design of pharmaceutical formulations under control.

14.21.1.2.2.2 Areas of utilization

Solvents including water are used in different ways in pharmaceutical formulation:

•either as a part of the final drug product: injectables,

drinkable solutions, patches, sprays, microemulsions

•or used as an intermediary vehicle which is removed at the end of the process: granulation

coating sugar coating

microencapsulation

We have listed in Table 14.21.1.4. the most commonly used solvents.

Table 14.21.1.4 Solvents used in formulation

Manufacturers try progressively to replace the formulations using organic solvents such as chloroform, dichloromethane, cyclohexane belonging to the class 2 (ICH classification see Chapter 16.2), for example by developing aqueous coatings.

14.21.1.2.2.3 What should be the quality?

Taking into account the fact that the solvents used in the DP manufacturing process, either as a component of the formulation or as a residual solvent, will be absorbed by the patient, their quality must be of the highest standard. From a regulatory point of view, in almost every country if not all, it is mandatory to use solvents covered by a pharmacopoeial monograph (e.g., European Pharmacopoeia, USP, JP, local Pharmacopoeias). Some examples are given below.

14.21.1.3Impacts of the nature of solvents and their quality on the physicochemical characteristics of raw materials and DP.

14.21.1.3.1 Raw materials (intermediates, DS, excipients)

The impurities contained in the solvents could have several effects on the raw materials:

•When the solvents are removed, non-volatile or less volatile impurities will be concentrated in raw materials.

•They can induce chemical reactions leading to side products.

•They can affect the stability of the raw material considered.

•They can modify substantially the crystallization process.

14.21.1.3.1.1 Concentration of less volatile impurities

Due to the potential concentration of these impurities, they should be tested for in both DS and excipients and even in intermediates of synthesis if the latter constitute the penultimate step of the synthesis and if solvents belong to class 1 or class 2 solvent (see Chapter 16.2).

14.21.1.3.1.2 Side reactions

This case has already been illustrated (see paragraph 14.21.1.2.1.6.5). The skills of the chemist together with those of the analyst are needed to ensure that the presence of unexpected impurities can be detected. By way of example, the reactions involving the keto-enol tautomerism deserve to be mentioned. The equilibrium is very sensitive to the solvent so that the presence of other solvents as impurities in the main solvent can modify the keto-enol ratio leading to irreproducibility in the chemical process.13,14

14.21.1.3.1.3 Consequences for stability

Some solvents, as mentioned in the paragraph 14.21.1.2.1.5, can contain very active entities such as aldehydes and peroxides. For example, if the raw material contains primary or sec-

ondary amines and/or is susceptible to oxidation or hydrolysis, it is likely that degradants will be formed over the time, reducing potentially the retest date of the raw material. The same situation could affect the DP and therefore two examples are given in paragraph 14.21.1.3.2.

14.21.1.3.1.4 Solvent purity and crystallization

This issue is may be less known except for chemists working in this specialized area. Because the consequences can be important for the processability, stability and occasionally bioavailability of the drug substance in its formulation, it is relevant to comment on this subject.

14.21.1.3.1.4.1 Role of the nature and the quality of solvent on crystallization

Most of the drugs on the market are obtained as a defined crystalline structure and formulated as solid dosage forms. It is well known that a molecule can crystallize to give different crystalline structures displaying what is called polymorphism. The crystal structures may be anhydrous or may contain a stoichiometric number of solvent molecules leading to the formation of solvates (hydrates in case of water molecules). Pseudopolymorphism is the term used to describe this phenomenon.

Another characteristic which plays a major role in the overall processability of the DS for DP manufacture is the “crystal habit”. This term is used15,16 to describe the overall shape of crystals, in other words, the differing external appearance of solid particles which have the same internal crystalline structure.

Both structures (internal, external) are under the control of different parameters including the nature of the solvent used and its quality. The role of the solvent itself in the overall crystallization process, including the determination of the crystal structure and the crystal habit is well known.17 But it is equally worth noting that impurities coming from:

•the product to be crystallized

•the solvent used

•the environment

can selectively affect the nucleation process and the growth rates of different crystal faces.17-21 They can be selectively adsorbed to certain faces of the polymorphs thereby inhibiting their nucleation or retarding their growth to the advantage of others. Crystal shape (habit) can also be modified by a solvent without polymorphic change. Additives or impurities can block, for a defined polymorph, the growth rate of certain faces leading e.g. to needles or plates. It is possible to introduce deliberately additives to “steer” the crystallization process. An interesting example of this crystal engineering strategy have been published for e.g., adipic acid22 or acetaminophen.23

14.21.1.3.1.4.2 Solvent-solid association/overview

After the crystallization of the product, solvents must be removed in order to obtain the minimum amount of residual solvents compatible with safety considerations and/or physicochemical considerations including stability, processability and occasionally microbiological quality (see Chapter 16.2). Different situations can be encountered.

14.21.1.3.1.4.2.1 Solvent outside the crystal

The solvent remains outside the crystals at the time of crystal formation. It is adsorbed on the surface or in the crystal planes. In the first case, the solvent is easily removed. But in the second case, if a cleavage plane exists, the drying process can be very difficult. Two methods can be used to try to remove this type of residual solvent almost completely.

•Displacement by water vapor in an oven, keeping in mind that this method may introduce some degradation leading to processability problems.11,24

•Extraction by supercritical CO225,26 but the extraction power of CO2 is basically limited to slightly polar solvents.

14.21.1.3.1.4.2.2 Solvent inside the crystal

The solvent remains inside the crystalline structure. Three situations can arise. 14.21.1.3.1.4.2.2.1 Occluded solvents

During rapid crystallization, some degree of disorder (amorphous phases, crystalline defects) can arise, creating pockets where residual solvent can be occluded. Through a process of dissolution/recrystallization this “hole” moves towards the external faces of the crystal releasing the solvent at the end. This phenomenon is more frequent for large crystals (500 µm/600 µm) but rare for smaller crystals (1 - 100 µm). The solvent odor which is detected when opening a drum or a bag containing a substance which was dried in the normal way can be explained by this mechanism.

14.21.1.3.1.4.2.2.2 Solvates

At the end of the crystallization process, the substance can be isolated as a solvate (hydrate), i.e., as a pseudopolymorph. The solvates generally have quite different physicochemical properties from the anhydrous form. Their stability can be questionable and in any case deserves to be investigated. In some cases it is possible to remove the solvent from the crystal without changing the structure of the lattice leading to an isomorphic desolvate which displays a similar X-ray diffraction pattern to that of the parent compound.2,27 The lattice of the desolvated solvate is in a high energy state relative to the original solvate structure. A better dissolution rate and compressability can be expected,28 but the drawbacks are hygroscopicity and physico-chemical instability. The lattice could undergo a relaxation process over time which increases the packing efficiency of the substance by reducing the unit cell volume.

When developing a new chemical entity all these aspects have to be considered to avoid unpleasant surprises during development or once the drug is on the market. Due to the need for process scale-up and of making the manufacturing process more industrial, changes are introduced especially in the crystallization and the drying processes, (e.g., change from static drying to dynamic drying). Because the drying is a particularly disturbing process for the integrity of the lattice, defects and/or amorphous phases may be created favoring subsequent polymorphic or pseudopolymorphic transformations of the crystalline form developed so far, if it is not the most stable one.

14.21.1.3.1.4.2.2.3 Clathrates

In contrast to solvates, clathrates do not show any stoichiometric relationship between the number of molecules of the substance and the number of molecules of solvent. Clathrates actually correspond to a physical capture of solvent molecules inside the crystal lattice without any strong bonds including hydrogen bonds. Molecules of one or several solvents can be trapped within the crystalline structure as long as the crystallization has been performed with a pure solvent or a mixture. The case of the sodium salt of warfarin giving “mixed” clathrates with water and isopropyl alcohol is well known and the existence of 8/4/0 or 8/2/2 proportions has been shown.11

It is fairly obvious that some powder properties like wettability can be modified by the formation of clathrates. Because their formation is not easy to control, some batch to batch inconsistency may be expected in this situation.

Figure 14.21.1.1. DSC and TG patterns.

In order to demonstrate the internal character of the clathrate relative to the crystal lattice, the example of a molecule developed in the laboratory of one of the authors is given below.

Figure 14.21.1.1 shows the DSC pattern of a molecule with the melting event at 254°C and the corresponding TG pattern obtained at the same temperature scanning rate. At the time the melting occurs, a loss of weight is observed corresponding to the loss of 0.2 % of isopropanol. The nature and the amount of the solvent have been confirmed by GC after dissolving the substance.

14.21.1.3.2 Drug product

As for the DS, the solvents used for DP manufacture can produce some negative effects by themselves or through their own impurities.

For liquid or semi liquid formulations, the formulator has to ensure that the solvents themselves do not display chemical interactions with the DS or the excipients. Everything which has been said in paragraphs 14.21.1.2.1.5 and 14.21.1.3.1 remains true here.

14.21.1.3.2.1 Interaction of impurities contained in the solvent

As said in paragraph 14.21.1.3.1 with the DS, impurities contained in the solvent especially if they are strongly reactive, like aldehydes or peroxides, can promote formation of degradants. Regarding aldehydes, the publication of Bindra and all29 should be mentioned. It relates to the degradation of the o-benzylguanine in an aqueous solution containing polyethylene glycol 400 (PEG 400). This type of solvent very often contains formaldehyde, which can lead to the formation of a precipitate over time:

PEG can also contain peroxides which can initiate over time, the formation of degradants via an oxidation process. Several publications have dealt with this phenome-

non.30,31

14.21.1.3.2.2 Interaction with the container

When the formulation is a solution which is prepared from water and different organic solvents, it is mandatory to investigate possible interactions between the medium and the container especially if the latter is of polymeric nature (PVC-PVDC, polyethylene, etc.) with or without elastomeric stoppers. A thorough investigation is necessary including:

•an examination of the solution for plasticizers, antioxidants, monomers and oligomers, mineral impurities, potentially extracted from the container,

•the evaluation of the absorption by the container of components (DS, excipients)

contained in the solution.

In the first case, the migration of impurities into the solution could initiate physicochemical instability and possibly some potential toxicity.

In the second case, a decrease in the content of the DS and/or some excipient (e.g., organic solvents added to promote the solubility) could lead to some loss of therapeutic efficacy and in some case to physical instability (precipitation).

14.21.1.3.2.3 Solvates formation during the solid dosage form manufacture

During the granulation process it is possible that the DS (occasionally the excipient) could transform into a solvated crystalline structure (solvate, hydrate). During the drying process, different situations can occur:

•The solvate is poorly stable and the solvent is easily removed leading to either the original polymorphic form but creating a certain degree of disorder in the crystalline structure or to what is called a “desolvate solvate” form. In this last case, also named “isomorphic desolvate”, the desolvated solvate retains the structure of its parent solvated form. The X-ray diffraction patterns look similar between the parent and the daughter forms. In this situation we have the creation of a molecular vacuum which could substantially impact on the stability, hygroscopicity and mechanical characteristics of the DS and finally of the DP.

•The solvate is stable within the formulation: we then have in a sense a new chemical entity. The properties of the solvate could be entirely different (solubility, kinetics of dissolution, stability, processability, etc.) and the consequence could be either positive or negative. The case where the kinetics of dissolution are affected by the formation of solvates should always be investigated. Papers on this subject have been published for molecules such as lorazepam,32 hydrocortisone,33 cephalexin,32 etc.

•Obviously, as in the case of raw materials (14.21.1.3.1.4.2.2.3) clathrate formation should be considered in order to explain possible batch to batch inconsistency.

14.21.1.3.3 Conclusions

We have seen that the solvent, far from being inert, plays a key role by itself and occasionally via its own impurities in different ways which are important for pharmaceutical development. We will now discuss how to set up sound specifications for solvents in relation to their field of use.

14.21.1.4 Setting specifications for solvents

14.21.1.4.1 Solvents used for the raw material manufacture

For the raw materials we should distinguish between solvents:

•used during the synthesis

•and those used for the last step of the manufacture corresponding very often to the crystallization process.

As a rule of thumb, the specifications set for solvents used for the crystallization step will be more stringent than those used during the synthesis.

For the intermediates of synthesis, if the origin of the solvent is under control (e.g., existence of contracts/Quality Assurance audits) a simplified monograph is completely adequate (see Table 14.21.1.5) as long as the supplier provides a detailed certificate of analysis where impurities (including solvents) are properly specified with acceptable limits. If the same solvent is used for the crystallization step additional purity tests are necessary (Table 14.21.1.6).

For economic reasons, it may be necessary to recycle solvents. If so, the containers should be fully identified in terms of storage:

• If solvents can be efficiently purified (e.g., by redistillation) they must comply with the same specifications as those of fresh solvents and consequently can be used in any

not more than

synthesis.

• If they still contain volatile impurities resulting from the reaction they come from, they can be recycled only for this reaction. In this case, the impurities should be identified and their possible impact on the reaction evaluated. In Tables 14.21.1.7 and 14.21.1.8

we have summarized possible specifications for a fresh batch of ethyl acetate used for a defined chemical reaction and those for the recycled solvent.

We recommend working with reliable solvent suppliers who can give every assurance on the quality of solvents provided to avoid any “unpleasant surprises”.

Water should be mentioned separately. If it is used during the synthesis of intermediates the quality “drinking water” can be used without any problems. But if water is used during the last step of the process, its quality must be in compliance with the requirements of purified water as they are described in several pharmacopoeias. In Table 14.21.1.9 the requirements for the Ph. Eur and USP are given as examples. Purified water is generally obtained from the drinking water. It undergoes demineralization by either distillation or an ion-exchange process. Particular attention has to be paid to microbiological quality.