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SINHA ROY, P. (2017). Synthesis and Formulation of (R)-Tolterodine-L-Tartrate. PHILICA.COM Article number 1156.

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Synthesis and Formulation of (R)-Tolterodine-L-Tartrate

PARTHA SINHA ROYunconfirmed user (Pharmaceutical Science and Engineering (Process Chemistry & Chemical Technology), University of Leeds)

Published in chemo.philica.com

Abstract
Manufacturing aspects of R-Tolerodine L-tartrate are presented. Initially, five routes are selected for the synthesis of the product but later based on the criteria related to number of steps, cost of reagents, total time required, environmental conditions, purification methods and yield it is found that two of the routes are the most suitable to obtain Tolterodine. Hence, a re-evaluation is made over these two routes in terms of process complexity as an additional criterion which helps select one route as the most feasible one in terms of scale-up in manufacturing process development for R-Tolterodine Ltartrate. The report also explores on the unit operations required to develop the process in which the choice of equipments are made on the basis of cost, efficiency and possible hazards. The entire unit operations and equipments are presented in a form of process flow diagram clearly indicating the reagents, equipments, product, by-products, wastes and the way they are handled in context to the safety issues related to them. The process chemistry is analysed with detailed manifestations on the reaction types, kinetics and thermodynamics giving emphasis on risk assessment and challenges on scaling up the processes. Finally, a thorough discussion is made highlighting the matters regarding the formulation of R-Tolterodine L-tartrate into tablets and capsules.

Article body

1.      INTRODUCTION

 

Currently, the companies working in the manufacture of fine chemical compounds, e.g. drug compounds, work with teams formed by expert scientist and engineers to develop and improve the manufacturing processes making them more efficient and profitable. This means that during the design and development of a process, it is very important to make best decisions and select the best options using the knowledge and technology available. This project report involves the conceptual design of a process and a plant for the manufacturing of Tolterodine, using a suitable and effective chemical process, considering some of the most important aspects related to the development of a new process that can compete with the processes currently used by other companies for the obtaining of the same compound.

Tolterodine is an antimuscarinic drug used mainly to treat urinary incontinence caused by overactive bladder. This disease affects millions of people around the world decreasing their quality of life and is more common in women than men. Tolterodine was originally synthesised and patented by Pfizer, being currently marketed in Tablets of 1 or 2 mg for immediate release and extended release capsules of 2 or 4 mg. Currently in some countries, e.g. China and India, the process to produce tablets of Tolterodine is out of patent and in others e.g. United Kingdom, United States of America, the patent has already been expired (September 2012), giving the opportunity to other companies to formulate it and sell it. All this information confirms that if a robust process for the obtaining of Tolterodine is developed and implemented, the chances of generating a profitable company are huge, making it an attractive option for a new business. The objective of this project is to develop a new original process for the manufacture of Tolterodine, that is suitable for scaling-up to an industrial scale considering the chemical and engineering aspects, the cost of reagents and operations to make it profitable, minimising the environmental impact and health and safety risks and suggesting a location where the process can be implemented. Additionally a detailed review of the uses and applications and the formulation of Tolterodine in a suitable pharmaceutical form can be discussed and illustrated. To reach the objective, the report is divided into different chapters, each one is focused in a different aspect of the process, but all of them are connected and related altogether. In chapter 1 titled process route evaluation and selection, various routes for the synthesis of Tolterodine are identified and reviewed in detail considering its potential to be used in an industrial scale, the criteria for the evaluation of the routes are established and the evaluation of the routes is performed, permitting to select a route that will be the basis of the manufacturing process. In chapter 2 titled process flow diagram and evaluation/selection of appropriate unit operations, the suitable unit operations and equipments required to carry out the synthesis of Tolterodine in an industrial scale are selected and connected together to generate a detailed process flow diagram. The chapter 3 of the report, titled process chemistry, operational procedures and control includes a detailed analysis of each step of the selected synthetic route, so that all the side reactions, byproducts and challenges during the process are listed together with the controls and solutions to possible and undesired problems. Despite the fact that some modifications to the route have been made to minimise the possible complications, there are still some challenges in each step. Finally in chapter 4, titled product formulation, different alternatives to formulate Tolterodine into a suitable pharmaceutical form are defined and analysed.

 

2.      CHAPTER: PROCESS ROUTE EVALUATION AND SELECTION

 

The aim of the development of a process to obtain R-Tolterodine L-tartrate is based on the fact that it has potential to be marketed and compete with other manufacturers of the same compound generating the existence of a profitable company, anyway, before starting the planification of the manufacture, it is necessary to select the most convenient synthesis route to produce the desired compound. There are reported in the scientific literature several routes to synthesise the molecule of Tolterodine and any derivate that can be easily transformed to R-Tolterodine L-tartrate, however, each one of this route has different advantages and disadvantages according to the criteria of the team in charge of the development of the manufacturing process; once the criteria have been established it is possible to analyse each synthesis route to evaluate and decide which is the one that offers the most quantity of advantages and the minor number of disadvantages.

The criteria established for the evaluation or the routes are:

? Number of steps: To have a minimum number of chemical reaction steps is desired, because it indicates and approximate number of intermediates and reactors required, affecting the cost of the process and the time and human resources needed.

? Cost of reagents: The required raw materials must be readily available in the market and the price of those materials must be reasonably affordable to make the process be profitable.

? Safety: The reagents to be used in the synthesis process must be compatible in terms of handling and should not be highly reactive or corrosive, lethal or explosive, the properties of the materials must allow an easy handling by the employees and equipments. Also the impact to the environment must be kept as minimum as possible.

?Yield: The maximum percentage of yield is preferred, because it is related to the quantity of raw materials that will be needed to produce a desired amount of Tolterodine.

? Time required: The time for the synthesis to be done should be the minimum possible to enable a faster production and higher quantity of products produced in a fixed period of time.

? Environmental conditions: Any reactions which can undergo at room temperature or an optimum temperature (not too high or not too low) is generally preferred, because in the industry the changes of temperature involve the use of energy and controls, increasing the cost of the process

? Purification process: To reach the highest purity easily is appreciated and the method to purify the process must be easy to be scaled-up and do not require a long period of time.

 

2.1  Description of routes to obtain Tolterodine

 

At first, five synthesis routes were taken from different literature resources to be considered and analyzed to select which is the most suitable for a scale-up for the production of Tolterodine. These routes are described below:

 

Route 1:

In this route, there are 4 reaction steps to carry on for the production of (S)-Tolterodine. Compared with the other synthesis routes, it is not so much steps to process. Therefore, although all of the materials used in the process are available, it costs quite lots of money (around £658.4) to purchase them for synthesis in the laboratory scale. For the safety, it might cause a toxicity problem during the handling of the Cy2(Me)N. The yield of the final product is around 73%, being an advantage of this route. However, it is taken around 100hours for the whole synthesis which is the most time-consuming synthesis route compared with the others. For the whole process, the required pressure and temperature are so general. It is only pressurized with 5 atm of H2 and the temperature range is between -28 and 98°C. Furthermore, despite the fact that the purification process is needed in each reaction steps, all of the purification methods are so simple such as crystallization, refluxing and solvent extraction.

 

Route 2:

This route of synthesis comprises of five steps. The reagents used in this synthetic route have standard toxicity. The total time needed for completion of all the reactions in this synthesis is around ten hours, being one advantage of this route. One disadvantage is that the reactions in the whole process take place from room temperature to - 78° C, this means that different cooling systems will be required, increasing the complexity and cost of operation. The yield at the end of all the steps in the synthetic route is high, being around 91%, but two important disadvantages of this route is that the reagents are expensive and that the product obtained requires a long and complicated purification process consisting in a extraction and a long process of column chromatography.

 

Route 3:

The main advantages of this route are that the sodium borohydride, which acts as a powerful reducing agent and is also mild and not so expensive, is used in the place of lithium aluminium hydride which is more expensive; the reaction process takes place under reasonably workable and mild ambient conditions; between 0 and 1300C; good chemoselectivity is achieved in this process, observed when the oxygen lone pair that is in resonance with aromatic rings forms a higher carbonyl bond order in phenyl esters than in the accompanying ethyl esters which makes addition of hydride, from sodium borohydride, to the more reactive phenyl esters faster and it involves a simple purification process.

The disadvantages of this route are that it involves a large number of steps (seven); the cost of the starting materials is high relative to other routes; the overall yield of the process is not so much (61%) and it takes a relatively long time for the reaction to come to a halt (65hours).

 

Route 4:

This synthesis route begins with reduction of ethyl benzoylacetate that can easily be substituted by anhydrogenation, which produces byproducts that do not have a significant environmental impact and then followed by nosylation and Friedel-craft alkylation of intermediates, in this part it is possible to use an Total steps to obtain racemic mixture of tolterodine are 4 steps. Cost of reagent is relatively low when compare with the other routes. None of extremely hazardous reagents and intermediates are involved in this route, hence, safety score is average. Total yield is 62% which is relatively low. Reaction time in laboratory scale is 8 hours. Two steps react in room temperature, one step required to be cooled to 0 to 50C and another step required high temperature to reflux. Purification process is achieved by column chromatography which is considerably simple in laboratory scale but not in industrial scale due to time consuming and cost is relatively high.

 

Route 5:

The route 5 considers only 3 chemical steps, which is a low number compared with the other routes; however, it has to be considered that each one of these chemical steps involves two or more different unit operations which include as example distillation, filtration and separation. Advantages of this route are the low cost of reagents and high yield (72%) compared with the other routes and that the issues concerning the safety are not very significant. In the other hand, the main disadvantages in this route are that the time cycle is long (24 to 36 hours) and during the process can be noticed that the temperature has to be increased and decreased (from-25 to 125 °C) frequently and if this process has to be carried out in industrial scale that variations and controls of temperature involve the use of a big number of monitors and controls.

 

2.2  Evaluation of routes

 

According to the analysis made to each route a comparative table including all the criteria and the scores allocated for the research team can be seen in Table 2.5.1. In the table it is seen that the scores obtained by the routes 4 and 5 are the highest, being 41.2 and 40.0 respectively, the difference between the scores is not significant, it means that according to the criteria considered in the evaluation, both routes have in average similar equilibriums between advantages and disadvantages. However, the final product of the routes evaluated until this part is tolterodine, being the final product of the synthesis 4 a racemic mixture of tolterodine and for the synthesis 5 is R-Tolterodine hydrochloride, but the final product that wants to be synthesised is R-Tolterodine L-tartrate, which isthe salt used for secondary manufacture of pharmaceutical products, it means that additional steps have to be carried out to reach the desired compound. Being completed the original synthesis including the steps required to synthesise R-Tolterodine Ltartrate they can be reevaluated by adding as a new criteria the process complexity that the routes offer analyzing the unit operations each one requires to be used in industrial scale.

 

2.3  Description of routes to obtain R-Tolterodine L-tartrate

 

Steps in route 4 to convert Tolterodine racemic mixture into R-Tolterodine L- tartrate:

The potential difficulties found in the synthesis 4 are that there are two steps that involve separation of phases and it can be difficult to control in an industrial scale, also there were identified other processes such as drying, agitation and concentration that can easily be developed and the process of purification of the product involves column chromatography that could be substituted by a proper crystallisation.

 

Steps in route 5 to convert Tolterodine hydrochloride into R-Tolterodine L- tartrate:

In this synthesis, there are a lot of unit operations that are required to complete the synthesis. Also, it is seen that many changes in the temperature have to be done and in the industry it implies huge amounts of energy and controls. Another possible difficulty to scale up this route is the repetition of 2 or 3 times consecutives the same process, e.g. distillation or washing.

 

3.      CHAPTER: SELECTION OF UNIT OPERATION AND PROCESS FLOW DIAGRAM

 

3.1  Continuous Stirred Tank Reactor

 

The reactor must be used at the beginning of each step in order to allow the reactants to have a chemical reaction. Therefore, there are three types of reactors for choosing which are batch, plug flow (PFR) and continuous stirred tank reactors (CSTR).

In all of the steps, the continuous flow and large quantities of the materials are required for the industrial purpose so that the steady-state reactors are needed including PFR and CSTR. For all the steps, the CSTR is chosen because it can mix the reactants well. Also, the composition in the reactor is distributed uniformly in space and in time called the homogenous distribution. Furthermore, the conditions such as temperature and reaction rate are the same over the whole reactor. Meanwhile, those chemical reactions are exothermic but the temperature in those of reactions should be kept in the room temperature except the temperatures in steps 2 and 6 are kept between 0 and 5 degree celcius so the jacket involving heat exchanger should be included in those reactors for cooling. And the jacket is a metal tank to cover the whole reactor.

 

However, there are many types of heat exchanger such as plate-and-frame exchanger, spiral heat exchanger and shell-and-tube heat exchanger. Since the shell-and-tube heat exchanger is the most widely used in the industry, it is used. Also, there are many advantages for this type of heat exchanger which is shown as followed:

? The ranges of the thermal capacity and pressure are large.

? The heat transfer can be improved by the extended surfaces.

? The equipment cost is cheap because a wide range of materials can be chosen for the shell and tube.

? No extra cost was needed for cleaning and repair. [6]

 

3.2  Separator

 

Three separations of aqueous and organic phases are required in the process. One of the preferred options in the industry is distillation which, unfortunately, requires significant difference of boiling point of two phases aimed to be separated. Moreover, the increase of temperature to evaporate one phase must not produce an undesirable chemical reaction that modifies the phase that wants to be preserved to continue with the process.

When separation by distillation is difficult, an alternative is the liquid extraction where the contact between the phases must permit the transference of material, and also the densities and viscosities of the phases must permit an easy separation. Some of the equipments that can be used for liquid extraction include: mixer-settlers, packed extraction towers, perforated-plate towers, baffle towers, agitated tower extractors, pulse columns and centrifugal extractors. [7]

The equipment selected to carry out the separation is using a disc stack centrifuge. This centrifuge uses the difference between the density of the two phases and other factors such as viscosity, temperature, mutual solubility and selectivity to produce the separation of the two liquids.

The centrifuge has a vertical axis and a series of conical spaces stacked in the centrifuge rotor. Highspeed rotation produces the separation of the phases into two layers. The liquids are continuously fed and extracted when the layers have been formed. [8]

 

3.3  Agitated Filter Dryer

 

When the slurry is formed through the reactions of the produced organic phase with L-tartaric acid, it is to be separated and dried as well conveniently. Agitated filter dryer is preferred as drying through agitation helps generate attrition which typically makes the particles finer and as a result if this, these particles impart on better blending thereby influencing the overall manufacturing of the Active Pharmaceutical Ingredient. [9]

To remove the volatile solvents from the wet solid the slurry is subjected to undergo which results in the formation of dry granules. 2-propanol in agitated filter dryer is a useful combination as it impacts on flow-ability of the granular particles, exchange of heat and also the mixing within the dryer.

Agitated filter dryer is much preferred as t is suitable for continuous process as required in unit operation for Tolterodine. This dryer does not need the use of hopper the installation of which may even cost higher. Agitated filter dryer also provides large surface area for its drying chamber and hence there is a compatible provision for easy flow and transfer of heat in the required unit operation.

The advantageous part of choosing this dryer with 2-propanol system is that when the wall temperature within dryer gradually rises, it comes closer to the boiling point of 2-propanol (solvent) which in turn gives faster drying. [10] Apart from this, having the dryer and the filter together in single equipment can add benefits in terms of number of labour and cost.

 

3.4  Crystalliser

 

Crystallisation involves the evaporation and subsequent cooling of a solution to the point that it becomes supersaturated and forming crystals in the process. It includes purification and solid-liquid separation. In industrial process, this actually occurs in a crystalliser.

There are two types of crystallisers we can use in our process; the simple crystalliser or the fluidized bed crystalliser. The simple crystalliser is used for batch crystallisation while the fluidized bed crystalliser is used for continuous crystallisation.

A simple crystalliser is chosen to use in the process; the main reason being that the product is preferred to be crystallised out in batches unlike the fluidized bed crystalliser which recrystallises out continuously and that is not necessary in this process. Also, the fluidized bed crystalliser is larger compared to the simple crystalliser and it is more expensive to purchase.

The simple crystalliser comprises of a stirred tank, a calandria type heat exchanger and a cooling coil. The tank is charged with a solution and then steam is applied to the shell side of the heat exchanger and the solution is heated until it becomes saturated. The solution is cooled by water passing through the coil and the crystals are formed.

The simple crystalliser is preferred rather than fluidised bed crystalliser due to fluid bed crystalliser can operate the continuous crystallisation and use up high energy to generate pressure while operation.

 

3.5  Condenser

 

Condenser is used in the process to recover the ethyl acetate to be used in a reflux system. There is either a surface condenser or a contact condenser to choose. In a surface condenser, the coolant does not come in contact with the condensate or vapours while in the contact condensers, the coolant comes in contact with the condensate and vapours, and they are intimately mixed making them difficult to separate.

A surface condenser is preferred for the process, most importantly for the fact that the ethyl acetate can be recovered to reuse in the process so that it is unmixed with the coolant in the condenser.

Although, contact condensers are more flexible and less expensive than surface condensers, surface condensers usually require far less coolant (usually water) than the contact condensers.

 

4.      CHAPTER: PROCESS CHEMITSRY

 

This section describes each step of the selected route of manufacture of R-Tolterodine-L-tartrate, the challenges that are encountered in each of them and how they can be avoided or controlled. Also, the modifications made to the selected route of synthesis are also explained with reasons why they had to be modified.

 

STEP 1

For step 1 in the synthesis route, the ethyl benzoate is reduced to secondary alcohol. Originally, it can be reduced by sodium borohydride and methanol which is proposed. [4] In this reaction, borane (BH3) and sodium salt (MeO- Na+) are formed as by-products which could be removed by adding hydrochloric acid and water. However, there is the alternative reaction by using transfer hydrogenation in which sodium hydroxide and a mixture of [RuCl2(?6-mesitylene)]2 and [(S,S)-Ts- DPEN, 1] under nitrogen(11)as catalyst is preferred due to none of salt are formed instead of acetone formed.

Firstly, [RuCl2(?6-mesitylene)]2 and [(S,S)-Ts-DPEN, 1] are reacted together at 80oC for 20 minutes under argon which is acted as catalyst for the further transfer hydrogenation reaction. Secondly, ethyl benzoate dissolved in 2-propanol with the mixture of Ru(II) complex is reacted with sodium hydroxide at room temperature. As a result, 1-phenylpropane-1,3-diol and the acetone are formed.

 

Meanwhile, there are several operational factors including enantioselectivity, reaction rate, reversible problem and the solvent selection which are challenging the engineers and chemists during the scaleup process.

The reason why the transfer hydrogenation method is used by using the chiral Ru(II) complex but not the hydrogenation by using hydrogen gas is that the former method will not cause the enantioselectivity problem. In case of using the hydrogenation method, since the two intermediates with the same molecule but different conformers are formed which is due to the rotation of the functional groups around the C-C bond, the enantiomers are formed as a result. If it is the case, the chemists should figure out the extra step for separating the enantiomers such as resolution or chiral auxiliary for purification. It is not good, not only because the yield is reduced but also the capital cost is increased. However, the chiral Ru (II) complex is used as a catalyst to increase the enantioselectivity.

Meanwhile, the type of chiral Ru(II) complex used will affect the kinetic of reaction and the stereoselectivity due to the bulkiness and electronic properties of the substituent in the Ru(II) complex. The more bulky the complex is, the lower the reactivity because the bulk complex is difficult to approach the target molecule. Furthermore, the reactivity is decreased with increasing the ability of electron-withdrawing substituents in the Ru(II) complex. For example, there are several substituents which are in the descending order of reactivity: C6H5CO > p-CH3OC6H4SO2> C6H5SO2>

CF3SO2. By the way, the sulfonylatedRu(II) complex is given the higher stereoselectivity. However, [RuCl2(?6-mesitylene)]2 is used in this step because it is reactive.

For the problem of reversibility, it is the most challenging problem that the engineers and chemists need to deal with. Also, it is related to the thermodynamic condition. If it is thermodynamic favourable, the product is favourable to form. Moreover, it is influenced by the structure of the reactant, hydrogen donor and the reaction condition. Thus, they need to do many experiments to find out what conditions are going to favour the thermodynamic condition. During the reaction, the solvent is used as a medium for the reaction carried out. Actually, there are two solvents that can be used which are 2-propanol and formic acid. For the safety and reactivity reasons, the 2-propanol is used. Although both are organic solvent which is flammable, 2-propanol is less toxic and does not cause any skin corrosion at all.

 

STEP 2

In step 2 of the process route, 1-phenylpropane-1,3-diol is reacted with 4-nitrobenzene sulfonyl chloride and triethylamine to produce 3-hydroxy-3-phenylpropyl-4-nitrobenzene sulfonate as the desired product and hydrochloric acid and triethylamine again are given off as by products.

This reaction is an exothermic reaction and therefore requires cooling to prevent an explosive reaction. Cooling is achieved in the process set-up by employing the use of a heat exchanger around the reactor in which the mixture is taking place. This heat exchanger is set to maintain a temperature between 0 and 50C to achieve as low a temperature as possible. Dichloromethane that was initially used on the laboratory scale was eliminated on the large scale due to its volatility. Compared to reactions in the laboratory, a large scale process will require more amounts of the reagent therefore increasing the risk of dangerous reactions and also emission of chlorine gas into the environment.

The reaction that occurs in this step undergoes an SN2 reaction. The nucleophile (which in this case is the Ns group) attacks the carbon attached to the OH group and causes the hydrogen to leave and then bonds to the carbon. The bond breaking and making occurs at the same time. This reaction should occur at a relatively fast rate because of the high concentrations of the 1-phenylpropane-1,3-diol and the NsCl. However, some time will be required in the protonation of the OH to make the bond easier to break.

The by-products formed in the reaction, HCl and Et3N, are acid and base respectively and will react to form triethylamine hydrochloride, a white odourless solid which will be soluble in 2-propanol from step 1 due to its ability to be soluble in alcohols. This makes the removal of the waste from the process less difficult as it can be passed out through a pipe from the reactor.

Extra measures, such as effective by-products removal techniques, should be taken in the handling of the by-products, as HCl is a very reactive compound. An explosive reaction might occur if it reacts with the 2-propanol, probably due to excess 2-propanol in the reactor. To prevent this, the amount of 2-propanol in the reactor is crucial and therefore, the exact right amount of it to be used in the process should be calculated to be just right to avoid excess. This is also discussed in more detail in the health and safety section of this project.

 

STEP 3

In this reaction 3-hydroxy-3-phenylpropyl-4-nitrobenzene sulfonate reacts with diisopropylamine to give the product 3-(Diisopropylamino)-1-phenylpropan-1-ol. Primarily NsOH is produced as a byproduct along with the product and then it is allowed to react with Brine solution (NaCl) which is mainly used to separate the product from NsOH. By the end of the reaction NaONs is produced with the formation of hydrochloric acid.

3-hydroxy-3-phenylpropyl-4-nitrobenzene sulfonate undergoes substitution reaction through

substitution nucleophilic bimolecular where bond breaking and bond forming occurs at the same time. Diisopropylamine here serves the purpose of being a very useful nucleophile as low boiling point (83- 85°C) of it can be typically beneficial for this reaction to act as a chamber of heat to move and run the whole reaction under optimally low temperature. 2-propanol, on the other side, is the solvent being used from the previous step.

2-propanol is miscible with water and hence it can be separated from water by means of a centrifuge.

The centrifugal force makes the separation fast and the insert on the centrifuge vessel shortens the settling path. Thus a higher throughput capacity is achieved. Nonetheless, whatever be the volumes of the liquids 2-propanol and water, they are beautifully clarified and separated in the same period of time. As 2-propanol has low boiling point (80-83°C) and a high vapour pressure [951 mmHg at 80°C], so when it is subjected to high temperature at a specific extent, it becomes flammable. To check this type of experimental hazards, heat must be applied in a specifically controlled manner to manage the problems of high amount of solvent evaporation and drying of the reaction vessel. [12],[13]

Temperature control is a seriously important aspect here. For this reaction it is necessary to check the temperature of the reaction vessels as the reaction being exothermic gives rise to heating of the vessel. As a consequence, if this reaction runs with relatively high temperature (above 85-100° C) that will increase the rate of the reaction and rapid generation of heat can cause problems like explosion. In this reaction, as the starting material which undergoes substitution will lead to a decomposition of the product if the temperature remains high. Hence, for refluxing it is preferred to maintain the temperature at a range of 70-75°C which is below the boiling point of 2-Propanol. [6]

Reflux facilitates this reaction and allows the temperature control through the solvent boiling point (80-83°C). (6) Reflux facilitates this reaction as it allows run the reaction through a specific heating for a certain period of time (around 3 hour) because the vapour which is formed back into the liquid form is cooled down in a continuous manner. The vapours which are formed above the reaction are condensed continually. This confirms the reaction to remain under a static temperature. Thus solvent (2-propanol) is recycled through the refluxing. [13]

 

STEP 4

In step 4, 3-(Diisopropylamino)-1-phenylpropan-1-ol is reacted with p-cresol and 70% aqueous solution of perchloric acid as acid work-up reagent to obtain desired racemic mixture of tolterodine and perchlorate (ClO4 -), as by product. Sodium hydroxide is added to neutralised perchlorate by forming salt which dissolve in both water and 2-propanol, but could be separated from racemic mixture of tolterodine which is dissolved in 2-propanol by centrifugal separator.

The mechanism of reaction is SN1 which is nucleophilic substitution of carbo-cation intermediate of 3-(Diisopropylamino)-1-phenylpropan-1-ol by p-cresol. The reaction is first order reaction which mean rate of reaction solely depends on concentration of 3-(Diisopropylamino)-1-phenylpropan-1-ol. Acid work-up used in laboratory scale was 70% perchloric acid in aqueous solution which as known as strong acid and strong corrosive which should be consider in health and safety issue in large scale production. Moreover, the waste generated from this reaction is Perchlorate ion which is needed to be meticulously controlled in waste management. Due to perchlorate affects human health, especially pregnant and children, by disturbing thyroid gland. Hence, to minimise hazardous issue, other acid workup should be used, for instance acetic acid, citric acid, or sulphuric acid. Meanwhile, further experiment about other acid workup should be conducted by consider about side reaction that might occur.

Solvent in SN1 reaction should be polar and protic solvent to stabilise carbocation intermediate, moreover to solvate the leaving group which is water in this reaction. The solvent using in this step is 2-propanol which is polar and protic solvent and can dissolve reactant given homogenous reaction. On the other hand, 2-propanol has relatively low boiling point, 82oC, and this reaction is high exothermic. Hence, temperature should be carefully controlled and monitored, as specified at 25oC, to avoid boiling of solvent and degradation of product.

 

STEP 5

The last chemical step involves the obtaining of the final desired product, R-Tolterodine L-tartrate starting from the racemic mixture of Tolterodine base obtained in the previous step.

To carry out the reaction L-tartaric acid is dissolved in 2-propanol at room temperature into a continuous stirred-tank reactor, it is important to notice that one property of this acid is that it is soluble in alcohols at room temperature. Once the solution of the acid is contained in the reactor, the organic phase containing the racemic mixture of Tolterodine base must be added all at once preferably or as fast as possible to form a slurry, if the addition is not done quickly, there is a risk of having mixing difficulties and unreacted material, affecting the yield and the time of the process.

Once the slurry is formed in the reactor the temperature must be decreased to 0±5oC using a cooling jacket, ensuring that all the mixture contained in the reactor stays in that temperature for about 5 hours is important, in this step the crystal formation will start, it means that the speed of the stirring must be constant during the cooling. In this step different studies must be done to analyse which is agitation speed required to obtain the size and shape of crystals desired.

After about 5 hours of maintaining the temperature in the reactor between 0±5oC, the salts of the two enantiomers of Tolterodine (R-Tolterodine L-tartrate and S-Tolterodine L-tartrate) can be separated washing, filtering and drying the slurry, this will achieved using as equipment an agitated filter dryer and as solvent 2-propanol, the temperature to dry is about 60 oC.

Finally, the purification of the R-Tolterodine L-tartrate is achieved by recrystallisation in 2 -propanol dissolving the crystals at room temperature and later evaporating the solvent at 60 oC to recover the crystals. The method of resolution is used to obtain the desired salt of the desired enantiomer of Tolterodine (R-Tolterodine L-tartrate); the basis of this reaction is that Tolterodine being a base can react with an acid to give a salt, the reason for selecting L-tartaric acid is that the L form of the acid is the one that is naturally found and that the salt produced with it is the currently accepted to treat urinary incontinence.

The advantage of using the salt resolution to obtain the R-Tolterodine L-tartrate is that both the resolution and the salt formation are carried out in just one step. However the main disadvantage is that, being only the salt formed with the R-enantiomer the desired, the maximum yield in this step is 50%.

The process is not too complex, but there are a few challenges which are possibly encountered which have been duly discussed. The main challenge in this process can be said to be the use of 70% perchloric acid, but with further research on this subject, a replacement reagent may be developed to substitute its use.

 

5.      CHAPTER: PRODUCT FORMULATIONS

 

The objective of producing Tolterodine is that it will be used as active pharmaceutical ingredient mixed with excipients and processed to obtain a pharmaceutical form suitable to be marketed and to treat urinary incontinence.

Considering that urinary incontinence is a disease that affects the quality of life of the patient, but cannot cause the death or has to be treated urgently, it is possible to consider the formulation of the Tolterodine in a pharmaceutical form for oral administration, which is the most common and convenient route for the administration of drugs, allowing to produce a systemic effect in a considerable short period of time after ingestion, depending on the properties formulation of the drug.

 

5.1  Salt selection

 

The way in which the salt selection is performed is based in the fact that Tolterodine is a basic compound and reacting with an acid permits the formation of a salt, however, not all the acids produce salts that are acceptable to be used for oral administration of drugs. The properties of the (+) L-Tartaric acid can be seen in the Table 2.9.5.1; with this information it is possible to understand why it is possible to consider the chance of using the salt resulting of this acid with Tolterodine base to be formulated into a pharmaceutical product.

There are several reasons that affect the salt selection of a drug compound, some of themare the following:

1. Improvement or control of dissolution rate of the drug

2. Polymorphic stability of the salt

3. Pharmacological properties

4. Extension of patent protection

5. Cost and efficiency during the synthesis of a drug. [29]

 

In the case of R-Tolterodine-L-tartrate the studies of all the properties (dissolution, stability and pharmacological properties) proved that it is a suitable salt to be administered orally, but an important fact is that in the synthesis selected in the present project the obtaining of the salt is also used as resolution to separate the R-enantiomer, which is the currently approved to be used in pharmaceutical formulations, doing this because the cost, time and complexity for the preparation of the desired salt are reduced.

 

From the properties and the structure can be noticed that the molecular weight (475.6), the partition coefficient (1.83) the number of possible H-bond donors (1) and of H-bond acceptors (1 are in the desirable range according to the rule of 5 of Lipinski, which is used to predict if one drug molecule will have good solubility and permeability when it is administered orally and indicates that the molecular weight must be less than 500, the number of H-bond donors less than 5, the number of Hbond acceptors less than 10 and the partition coefficient less than 5. [31] The information of solubility in water (12 mg/mL) confirms that it can be dissolved in the aqueous medium of the gastrointestinal tract and the melting point (205-210 °C of the R-Tolterodine-L-tartrate compared with 164-165 °C of the Tolterodine base) indicates that if the compound is exposed to increases of temperature in processes such as compression or drying during the manufacture of the oral formulations, the compound will not melt causing inconvenience.

 

5.2  Pharmaceutical form selection

 

Another important analysis performed when the salt of a drug molecule is a candidate to be used in the formulation of a drug product is the analysis of the polymorphic beahaviour of the compound. In the patent US 7,393,874 B2, there are reported four crystalline forms of R-Tolterodine-L-tartrate and one stable amorphous form and the methods for their preparation, nevertheless in the process developed in the present report the analysis of the behaviour and stability of the form of RTolterodine- L-tartrate must be performed to confirm that the properties are adequate to be used in the formulation and in the case of the obtaining negative results, the process could be modified to ensure that the polymorphic form obtained is suitable to be used in the formulation of a drug product. [12] Once that has been determined that R-Tolterodine-L-tartrate is suitable to be formulated in a drug product for oral administration, the first pharmaceutical form considered to be formulated is as a tablet. Anyway, before selecting the formulation route to prepare the tablets, pharmacological information of the R-Tolterodine-L-tartrate must be used to determine if the tablet must be of immediate or sustained release and to calculate the quantity of R-Tolterodine-L-tartrate that will contain each tablet.

The pharmacological effect of Tolterodine is that it acts as a competitive muscarinic receptor antagonist, affecting the bladder function and is metabolized in the liver to form a 5 hydroximethyl metabolite, which is also very active and produces the same effect in the organism.

Observing the pharmacokinetic behaviour of the R-Tolterodine L-tartrate, it is observed that when it is administered orally, the time to be absorbed, the generation of a metabolite that also produces the desired pharmacological effect and the routes used for metabolism and excretion confirm that the a suitable route to administer it is in oral tablets of immediate release. However, urinary incontinence is a chronic disease in most of the patients, it generates the need of a frequent administration of the drug product and one common alternative to avoid the frequent administration of a medicament is the formulation of the drug in a sustained release pharmaceutical form, being the preferred a tablet or a capsule if the route of administration is the oral.

 

5.3  Formulation route for tablets

 

Once it has been decided that the tablet for immediate release will be the first form in which the RTolterodine- L-tartrate will be formulated and clinical studies have been carried out to determine that the concentration of R-Tolterodine-L-tartrate in each tablet must be 1 mg or 2 mg and that concentrations for the sustained release formulation must be 2 mg or 4 mg in each tablet or capsule, the selection of the processes to manufacture the drug product has to start.

To produce tablets there are three principal route that can be used: wet granulation, dry granulation and direct compression; being the last route mentioned the currently preferred for the manufacturing companies of drug products, because it does not require unit operations to form granules of RTolterodine- L-tartrate with the excipients before compression reducing the cycle time and the cost of the manufacture of tablets. On the other hand if direct compression is selected, then the mixture of RTolterodine- L-tartrate with excipients must have good flowability and compressibility.

It is also important to consider that once the tablets are manufactured they can be evaluated if coating is required to protect the tablet, improve the appearance flavour or odour of the tablet or inclusive to modify the bioavailability. Considering that it is convenient to coat the tablets, a list of pharmaceutically acceptable excipients that can be mixed with R-Tolterodine-L-tartrate to form film coated tablets of immediate release are shown in theTable 5.. including a brief description, use and stage of the process in which the excipient is used. The equipments were selected according to the simplicity of operation and controls that can be implemented during the process to monitor the quality of the tablets.

 

5.4  Formulation route for capsules

 

Finally, about the sustained release solid formulation, the options are capsules or tablets, which according to the coating and composition of the tablets or of the composition of the gelatin and the powder that form the capsule the desired sustained release can be reached. One good option is formulating in hard gelatin capsules, which are formed of two pieces (cap, the shorter and body, the longer) of hard gelatin in form of cylinders that fit one in the other and contain the powder formed of the R-Tolterodine-L-tartrate and the excipients, that will also play an important role to produce the sustained release effect. [33]

 

5.5  Conclusion

 

In conclusion, R-Tolterodine L- Tartrate is a salt derived from Tolterodine that has different properties that make it suitable to be administered orally and formulated as film coated tablets for immediate release and as hard gelatine capsules for prolongued release; however, different routes, equipments and excipients can be employed to obtain the forms desired. In the future it is possible that new studies will allow the selection of a different compound of Tolterodine (salt, co-crystal, etc) to be formulated in the same or different pharmaceutical form (tablet, capsule, suspension, etc) offering a better behaviour profile of the drug in the body and/or reduction of cost and complexity during manufacture .

 

6.      CONCLUSION

 

To synthesise R-Tolterodine L-Tartrate 5 different synthetic routes for the initial obtaining of

Tolterodine were evaluated in detail and scored considering their number of chemical steps, cost of reagents, safety, yield, time required, environmental condition to carry out the reactions and the purification process of the product and according to the scores obtained the two routes with the higher score were completed using other chemical routes to obtain the desired salt (R-Tolterodine L-tartrate) and were re-evaluated adding as a key criteria the process complexity. Finally the route with the highest score, being the one that proved to be the most suitable to be scaled up and used in a new manufacturing process was selected.

The route selected involves the initial synthesis of the racemic mixture if Toltetodine base in four chemical steps and a fifth step for the resolution of the compound using L-tartaric acid to obtain the salt R-Tolterodine L-tartrate. To develop the process, an analysis of the unit operations needed was done and proper equipments were chosen according to the advantages of their operation and of considerations about their cost, efficiency and safety, resulting in the generation of a detailed diagram that considers all the inputs, outputs, transformations and operations of the whole process.

The process chemistry of the designed manufacturing process was reviewed and discussed in detail, identifying the important challenges during the scaling up of the process. In general, the most important issue involves the control of the temperature during the process to allow the reactions to be carried out but controlling the generated heat because all the reactions are exothermic. Other important issues identified were the risks related to the safety and environmental impact caused by the reagents and by-products and their handling through the process to avoid any kind of accident or critical environmental impact.

The consideration of the challenges identified in the process chemistry affected the final selection of reagents, unit operations and equipments involved in the process and also the establishment of important controls during the operation.

Finally, formulation of the R-Tolterodine L-tartrate highlighted that the most important current use is the treating of urinary incontinence and the preferred formulations are the immediate release tablets of 1 and 2 mg and the sustained release capsules of 2 and 4 mg.

 

7.      REFERENCE

 

1. ULGHERI, F., M. MARCHETTI and O. PICCOLO. Enantioselective synthesis of (s)- and

(r)-tolterodine by asymmetric hydrogenation of a coumarin derivative obtained by a heck

reaction. Journal of Organic Chemistry, 2007, 72(16), pp.6056-6059.

2. PARAS, N.A., B. SIMMONS and D.W.C. MACMILLAN. A process for the rapid removal of

dialkylamino-substituents from aromatic rings. Application to the expedient synthesis of (r)-

tolterodine. Tetrahedron, 2009, 65(16), pp.3232-3238.

3. JAGDALE, A.R. and A. SUDALAI. Co-catalyzed mild and chemoselective reduction of

phenyl esters with nabh(4): A practical synthesis of (r)-tolterodine. Tetrahedron Letters,

2008, 49(23), pp.3790-3793.

4. DE CASTRO, K.A. and H. RHEE. Selective nosylation of 1-phenylpropane-1,3-diol and

perchloric acid mediated friedel-crafts alkylation: Key steps for the new and straightforward

synthesis of tolterodine. Synthesis-Stuttgart, 2008, (12), pp.1841-1844.

5. JAMES R.GAGTE, P., MICH.; JOHN E.CABAJ, SHEBOYGAN, WIS. Process to prepare

tolterodine us patent number 5,922,914. Patent number: 5,922,914. Jul. 13,1999.

6. AL, K.E. Process for preparing tolterodine tartrate us patent us 2006/0194987 a1. Patent

number: Aug.31,2006.

7. MCCABE, W.L., J.C. SMITH and P. HARRIOTT. Unit operations of chemical engineering.

Mcgraw-hill chemical engineering series. 7th ed. Boston ; London: McGraw-Hill, 2005.

8. WILSON, I.D. and C. POOLE. Handbook of methods and instrumentation in separation

science volume i. San Diego, California: Academic Press, 2009.

9. KOUJOULOUS, E.E.A. Impact of agitated drying on the powedered properties of an active

pharmaceutical ingredient. Powdered Technology, 2011, 210(3), pp.308-314.

10. SAHNI, E.E.A. Quantifying drying performance of a filter dryer: Experiments and simulation

Advanced powder tecnhology, 2011, In Press.

11. HASHIGUCHI, S., A. FUJII, J. TAKEHARA, T. IKARIYA and R. NOYORI. Asymmetric

transfer hydrogenation of aromatic ketones catalyzed by chiral ruthenium(ii) complexes.

Journal of the American Chemical Society, 1995, 117(28), pp.7562-7563.

12. AL, B.P.R.E. Polymorphs of tolterodine tartrate. Patent number: Jul 1, 2008.

13. CO, P.P.U. Leaflet detrol obtained from dailymed current medical information [online].

[Accessed]. Available from: http://dailymed.nlm.nih.gov.

14. Materials safety data sheet [online]. 1997-2005. [Accessed 31st January]. Available from:

www.sciencelab.com/msds.

15. Suppliers of chemical raw materials [online]. 2012. [Accessed 31st January]. Available from:

www.chemexper.com.

16. Prices of chemical raw materials [online]. 2012. [Accessed 31st January]. Available from:

www.sigmaaldrich.com.

17. NEWMAN, D.K. and A.J. WEIN. Managing and treating urinary incontinence. 2nd ed.

Baltimore: Health Professions Press, 2009.

18. HASLAM, J. and J. LAYCOCK. Therapeutic management of incontinence and pelvic pain :

Pelvic organ disorders. 2nd ed. London: Springer, 2008.

19. XIA, Z.L., Z.Y. CHEN and T.W. YAO. An enantiospecific hplc method for the determination

of (s)-enantiomer impurities in (r)-tolterodine tartarate. Die Pharmazie - An International

Journal of Pharmaceutical Sciences, 2007, 62(3), pp.170-173.

20. ABERG, G. S(-)-tolterodine in the treatment of urinary and gastrointestinal disorders. Patent

number: US 6310103 B1.

21. PER-GORAN GILLBERG, S.S., SUE K. CAMMARATA. Use of tolterodine to treat

asthma. Patent number: US 6538035 B2.

22. FENN, D. and KEY NOTE PUBLICATIONS. Market review 2005. Pharmaceutical industry.

Hampton: Key note, 2005.

23. ADMINISTRATION, U.F.A.D. Orange book: Approved drug products with therapeutic

equivalence evaluations [online]. [Accessed]. Available from:

31

http://www.accessdata.fda.gov/scripts/cder/ob/docs/patexclnew.cfm?Appl_No=021228&Prod

uct_No=002&table1=OB_Rx.

24. The merck index : An encyclopedia of chemicals, drugs, and biologicals. 14th ed. Whitehouse

Station, N.J.Chichester: Merck ; John Wiley distributor, 2006.

25. COOPER, P.W.H. Nanjing investment environmental report, 2009. 2009.

26. KING, R.W. Safety in the process industries. Oxford: Butterworth Heinemann, 1990.

27. FURR, A.K. Crc handbook of laboratory safety. 4th ed / ed. Boca Raton ; London: CRC

Press, 1995.

28. Hse publishes guidance on the safe use and handling of flammable liquids. Journal of the

Society of Leather Technologists and Chemists, 1996, 80(3), pp.99-99.

29. STAHL, P.H., C.G. WERMUTH and INTERNATIONAL UNION OF PURE AND

APPLIED CHEMISTRY. Handbook of pharmaceutical salts : Properties, selection, and use.

Weinheim ; Chichester: Wiley-VCH, 2008.

30. CO, P.P.U. Leaflet of detrol la obtained from dailymed current medical information [online].

[Accessed]. Available from: http://dailymed.nlm.nih.gov.

31. LIPINSKI, C.A. Solubility and permeability in oral absorption: Prediction success depends on

chemistry structure. Abstracts of Papers of the American Chemical Society, 2005, 229,

pp.U610-U610.

32. ROWE, R.C., P.J. SHESKEY and M.E. QUINN. Handbook of pharmaceutical excipients. 6th

ed. London: Pharmaceutical Press, 2009.

33. AULTON, M.E. Aulton's pharmaceutics : The design and manufacture of medicines. 3rd ed.

Edinburgh ; New York: Churchill Livingstone, 2007.




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SINHA ROY, P. (2017). Synthesis and Formulation of (R)-Tolterodine-L-Tartrate. PHILICA.COM Article number 1156.


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