EA043692B1 - AMORPHOUS LETERMOVIR AND SOLID PHARMACEUTICAL PREPARATIONS CONTAINING IT, INTENDED FOR ORAL ADMINISTRATION - Google Patents

Description

Field of technology to which the invention relates

The technical field to which the invention relates is pharmaceutical chemistry/herbal preparations. The present invention relates to new stable galenic preparations containing an amorphous compound - Letermovir, intended for oral administration. These preparations are suitable for use as orally administered pharmaceutical agents for the treatment of viral diseases, in particular human cytomegalovirus (hereinafter referred to as HCMV) infections. The present invention also relates to methods for isolating Letermovir as an active pharmaceutical ingredient (hereinafter referred to as API) in an amorphous state. More precisely, the present invention relates to a powdered amorphous Letermovir having favorable physicochemical characteristics, such as particle size distribution, specific surface area and toxic impurity content, which makes this compound ready for inclusion in solid pharmaceutical preparations intended for oral administration.

State of the art

It is well known that when APIs in an amorphous state are used in the pharmaceutical industry, difficulties are encountered during their isolation and the preparation of the herbal preparation containing them. Particularly in the case of zwitterionic compounds such as Letermovir, which are known to exist in the form of various salts, many difficulties arise during the synthesis and preparation of the herbal preparation.

Letermovir is known to be a highly active drug for the treatment of HCMV infection and is described in detail in Lischka et al., In Vitro and In Vivo Activities of the Novel Anticytomegalovirus Compound Letermovir. Antimicrob. Agents Chemother. 2010, 54: p. 1290-1297, and in Kaul et al., First report of successful treatment of multidrug-resistant cytomegalovirus disease with the novel anti-CMV compound Letermovir. Am. J. Transplant. 2011, 11:10791084; and also in Marschall et al., In Vitro Evaluation of the Activities of the Novel Anticytomegalovirus Compound Letermovir against Herpesviruses and Other Human Pathogenic Viruses. Antimicrob. Agents Chemother. 2012, 56:1135-1137.

HCMV is a genus of virus belonging to the family of viruses known as Herpesviridae or herpes viruses. It is commonly referred to as HCMV, and is alternatively called human herpes virus-5 (HHV-5). Within the family Herpesviridae, HCMV belongs to the subfamily Betaherpesvirinae, which also includes cytomegaloviruses of other mammals.

Although HCMV infections can occur throughout the body, they are often associated with the salivary glands. HCMV infections are usually undetectable in healthy individuals, but they can be life-threatening in immunocompromised subjects, such as those infected with HIV (human immunodeficiency virus), organ transplant recipients, or neonates. In particular, HCMV remains a major virus causing birth defects and life-threatening illness in transplant recipients.

Current approved drugs with activity against HCMV target the viral DNA polymerase pUL54. A known compound, Ganciclovir (GCV), acts as a nucleoside analogue. Its antiviral activity requires phosphorylation by the HCMV protein kinase pUL97. In this case, Cidovir (CDV), as a nucleotide analogue, is already phosphorylated and, thus, is active. Foscarnet (FOS) has a different mechanism of action. It directly inhibits polymerase function by blocking the pyrophosphate binding site in pUL54. However, the above drugs are known to be toxic and resistance to these drugs is developing. In addition, it is necessary to improve their bioavailability.

Attempts have been made to develop more orally active and less toxic drugs with antiviral activity against HCMV combined with a new mechanism of action through the synthesis and evaluation of benzimidazole ribonucleosides. Drugs of this class have been shown to have high activity against HCMV and act on the viral terminase complex. However, it turned out that such compounds are metabolically unstable.

In addition, benzimidazole ribonucleoside-resistant HCMV has been described, where the resistance is associated with the viral open reading frames (hereinafter referred to as ORFs), UL89 and UL56 (see Krosky et al., Resistance of Human Cytomegalovirus to Benzimidazole Ribonucleosides-Maps to Two Open Reading Frames: UL89 and UL56, Journal of Virology, 1998, pp. 4721 - 4728, and Evers et al., Inhibition of Human Cytomegalovirus Replication by Benzimidazole Nucleosides Involves Three Distinct Mechanisms, Antimicrobial Agents and Chemotherapy, 2004, p. 3918-3927).

BAY 38-4766 is another active and selective inhibitor of HCMV replication and is a member of a new class of drugs with activity against HCMV, the non-nucleoside phenylenediaminesulfonamides. In addition, it affects the viral terminase complex. BAY 38-4766 prevents the cleavage of high molecular weight viral DNA concatemers to form genomic length monomers.

However, the development of such compounds was stopped.

In addition, HCMV-resistant compounds have been described that specifically contain mutations in the viral ORFs, UL56 and UL89 (see Buerger et al., A Novel Non-nucleoside Inhibitor Specifically Targets Cytomegalovirus DNA Maturation via the UL89 and UL56 Gene Products , Journal of Virology, 2001, pp. 9077-9086).

Other efforts to discover drugs with improved activity against HCMV have led to the identification of small molecular weight compounds, Bay 82-3286 and 3,4-dihydroquinazolines such as Letermovir.

Η N CN

CSM: BAY 82-3236

In contrast to the compounds described above, 3,4-dihydroquinazolines, such as Letermovir, block viral replication without inhibiting the synthesis of progeny DNA or HCMV viral proteins. In fact, the effects of Letermovir have been shown to be based on a mechanism involving viral terminase. However, its mechanism of interaction with the viral terminase complex and its chemical structure differ from those of all other currently characterized drugs known to target the HCMV terminase complex, including BDCRB and BAY 38-4766. While all published cleavage/packaging inhibitors, including BDCRB and BAY 38-4766, are described to have antiviral activity against rodent cytomegaloviruses, Letermovir only has activity against human cytomegalovirus and is thus highly promising as a a special drug with activity against human HCMV.

The exact chemical name of Letermovir is (S)-{8-fluoro-2-[4-(3-methoxyphenyl)-1piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro-4 -quinazolinyl}acetic acid represented by formula (I) below

Formula (I); i.e. C29H28F4N4O4.

The synthesis of Letermovir is described in US 2007/0191387A1, exemplary embodiments 14 and 15, pages 40 and 41, paragraphs [0495]-[0505]. Letermovir has excellent activity against HCMV in vitro and in vivo and has completed phase IIb clinical trials.

US 2007/0191387A1 does not describe the specific physicochemical characteristics of Letermovir, such as particle size distribution, specific surface area and pharmaceutically acceptable impurity levels, that make it suitable for inclusion in solid galenic preparations that can be administered orally.

The preparation of Letermovir is described in WO 2006/133822; example 11.

WO 2006/133822 does not describe the specific physicochemical characteristics of Letermovir, such as particle size distribution, specific surface area and pharmaceutically acceptable impurity levels, that make it suitable for inclusion in solid herbal preparations that can be administered orally.

WO 2013/127971A1 describes the sodium and calcium salts of Letermovir and their solvates, and their use as antiviral agents. WO 2013/127971A1 does not describe the specific physicochemical characteristics of Letermovir, such as particle size distribution, specific surface area and pharmaceutically acceptable impurity levels, that make it suitable for inclusion in solid galenic preparations that can be administered orally.

Letermovir inhibits HCMV replication through a distinct antiviral mechanism that involves the viral terminase subunit, but which is distinct from other classes of compounds that are also known to target this enzyme complex (see Goldner et al., The Novel Anticytomegalovirus Compound AIC246 (Letermovir) Inhibits Human Cytomegalovirus Replication through a Specific Antiviral Mechanism That Involves the Viral Terminase, Journal of Virology, 2011, pp. 10884-10893).

However, zwitterionic Letermovir has chemical characteristics that cause difficulties in its use in the field of pharmaceutical chemistry. Due to these characteristics, Letermovir isolated in the zwitterionic form can be maintained in an amorphous state, while to obtain Letermovir in the form of salts with acids or bases, it can be crystallized with a limited number of counterions (see also German patent application 102012101673.9; German patent application 102012101659.3) .

To date, attempts to crystallize API-Letermovir in zwitterionic form in a reproducible manner and store it crystallized in a stable polymorphic form have been unsuccessful. Therefore, Letermovir must be isolated in an amorphous state in sufficient yield and purity, while maintaining its physicochemical characteristics that provide dissolution parameters that make it possible to include it in a tablet/capsule preparation intended for oral administration.

In this regard, only such preparations containing Letermovir as solutions are known in the art. However, amorphous Letermovir, intended for the preparation of drugs suitable for intravenous administration, is completely soluble in water (wt./wt.) and in ethanol (wt./vol.) only with the addition of an excess amount of arginine or lysine, or with the addition of cyclodextrin in combination with sodium hydroxide.

The object of the present invention is the preparation of rapidly dissolving solid dosage forms, such as tablets and/or capsules, containing Letermovir in an amorphous state, suitable for oral administration. In this regard, another object of the present invention is the preparation of dosage forms containing solid amorphous API-Letermovir, intended for oral administration and providing sufficient bioavailability.

However, wet granulation using an aqueous solution of Letermovir and excess arginine, carried out by both spray granulation and high shear granulation techniques, does not provide a tablet/capsule that has sufficient solubility to provide immediate release (below in the present invention designated as IR). In particular, difficulties arose in isolating Letermovir as a pure API; purity and/or chemical stability in the case of the use of most organic solvents, including lower alcohols, were insufficient. Thus, contrary to expectations, the method of preparing drugs for intravenous administration using the addition of arginine is not applicable for the preparation of drugs containing Letermovir in the form of tablets/capsules. As shown in Example 1, arginine does not improve the dissolution characteristics of Letermovir contained in solid dosage forms.

The results of the dissolution study conducted by the present inventors also confirmed the presence of an unsatisfactory dissolution profile of amorphous Letermovir, since, as shown in Example 2, in the pH range of 1 to 7.5, the solubility of Letermovir varied from 0.4 to > 1 mg /ml.

Summary of the invention

The present invention has surprisingly provided pure powdered API-Letermovir in an amorphous state, which is suitable for subsequent processing into solid pharmaceutical preparations for oral administration. According to a dissolution study using Ph.Eur. (European Pharmacopoeia) method 2.9.3, Apparatus 2, at a blade speed of 50 rpm, at 37.0 ± 0.5 ° C in 1000 ml of 0.1 N medium. solution of HCl/0.2% sodium lauryl sulfate solution, and research using reverse phase HPLC (high performance liquid chromatography) for 30 minutes as described below, in the solid pharmaceutical preparations proposed in the present invention, the degree of dissolution of the amorphous Letermovir contained in obtained by granulation of the preparation, amounting to > 50% no later than after 30 min.

HPLC conditions:

Column: Waters Symmetry Nucleosil 100 C18, 40 mmx4.0 mm, 10 µm

Detection wavelength: 256 nm

Approximate 4 min experiment duration:

Approximate 1.3 min hold time:

Column temperature: 40°С Injected volume Flow rate: Mobile phase: 20 µl 1.5 ml/min pH 4.0 buffer/acetonitrile; 55/45 rev/rev

Accordingly, based on these improved dissolution characteristics, one would expect

- 3 043692 high bioavailability when administered orally.

The authors of the present invention have found that it is preferable if amorphous Letermovir can be isolated:

i) by roller drying a solution of amorphous Letermovir in a volatile organic solvent, preferably acetone, or ii) by precipitating amorphous Letermovir from water-miscible solvents (preferably acetone or acetonitrile) by adding to excess water used as an antisolvent.

In principle, amorphous compounds such as Letermovir can also be isolated by spray drying or evaporation of a solution in an organic solvent, but in the case of Letermovir, yields and/or purities were insufficient due to the very large amounts of residual solvent remaining in the amorphous API-Letermovir.

The inventors of the present invention have discovered two preferred methods of preparation, i.e. in the case of Letermovir isolated using a roller dryer, it is preferable if the API is processed by wet granulation, and in the case of precipitated Letermovir, it is preferable if the API is processed by dry granulation.

Both methods provide reproducible preparation of galenic preparations containing amorphous Letermovir as an API, in which, according to a dissolution study using the Ph.Eur.2.9.3 method, Apparatus 2, at a blade rotation speed of 50 rpm, at 37.0 ±0.5°C in 1000 ml of 0.1 N medium. solution of HCl/0.2% sodium lauryl sulfate solution, and testing by reverse phase HPLC for 30 min as described below, the degree of dissolution of the amorphous Letermovir contained in the granulated preparation is > 50% no later than in 30 min.

HPLC conditions:

Column: Waters Symmetry Nucleosil 100 C18, 40 mmx4.0 mm, 10 µm

Detection wavelength: 256 nm

Approximate 4 min experiment duration:

The approximate time 1.3 min holding: Column temperature: 40°С Injected volume 20 µl Flow rate: 1.5 ml/min Mobile phase: pH 4.0 buffer/acetonitrile; 55/45 rpm

Detailed Description of the Invention

The present invention relates to powdered Letermovir, which is in an amorphous state and is suitable for use in solid dosage forms for oral administration, wherein said Letermovir is characterized in that:

i) according to a BET (Brunauer-Emmett-Teller) specific surface area test, it has a specific surface area of at least 1 m ² /g and/or ii) according to a particle size distribution study, it has an average particle size distribution , constituting no more than 10 microns, which is obtained by a precipitation method, including the preparation of a solution of letermovir in water-miscible solvents selected from acetone or acetonitrile, and the precipitation of said letermovir from the solution with stirring in excess water, used as an antisolvent, followed by filtration or centrifugation to obtain the specified powdered amorphous Letermovir.

In addition, the present invention relates to solid pharmaceutical preparations that can be administered orally, containing such powdered amorphous API-Letermovir, which provide sufficient bioavailability, and are intended for use in the treatment of viral diseases, in particular for the treatment of HCMV infections.

The problems that need to be solved when preparing the appropriate galenic preparations based on amorphous Letermovir are related to:

a) mandatory isolation of it from solution in an organic solvent in order to obtain amorphous Letermovir in the form of a pure substance having physicochemical characteristics suitable for the preparation of preparations containing it for oral administration, and

b) by providing appropriate galenic preparations in which Letermovir is maintained in an amorphous state and this allows granulation to be carried out to obtain an IR tablet or capsule.

- 4 043692

In fig. 12 shows a reaction scheme representing the preferred synthesis route

Letermovira. In the diagram, the asterisk located in the lower left part before stage 4) - solvent replacement, indicates the stage at which the isolation according to the present invention begins.

In this regard, the present invention relates to solving the above problems, namely:

a) providing appropriate isolation techniques to obtain Letermovir in the form of a pure chemically stable substance and in an amorphous state;

b) providing an appropriate method for preparing a tablet/capsule containing amorphous Letermovir which has dissolution characteristics allowing its inclusion in IR dosage forms such as tablet/capsule, i.e. the degree of dissolution of Letermovir is > 50% no later than 30 minutes.

The present invention unexpectedly provides chemically stable orally administered solid pharmaceutical preparations containing Letermovir, characterized in that the degree of dissolution of the amorphous Letermovir contained in the granulated preparation is >50% after no later than 30 minutes.

In addition, the present invention unexpectedly provides chemically stable orally administered solid pharmaceutical preparations containing Letermovir, characterized in that the absolute bioavailability (F) of the amorphous API-Letermovir contained in the granulated preparation is from 30 to 95%, preferably from 50 to 95%, more preferably 60 to 95%.

Also unexpectedly, the present invention provides chemically stable orally administered solid pharmaceutical preparations containing Letermovir, characterized in that the absolute bioavailability (F) of the amorphous API-Letermovir contained in the granulated preparation is > 30%, preferably > 40%, more preferably >50%, even more preferably >70%, even more preferably >80% and most preferably >90%.

The chemical stability of a pharmaceutical agent is important to maintain its activity also when included in an administered dosage form, such as a tablet or capsule, intended for oral administration. One skilled in the art will know that the stability of an API depends, in particular, on the method of its isolation, as well as on the composition of the drug itself, its mixture, the method of its preparation and the conditions of its storage. In this regard, it is common knowledge that impurities may form during the degradation of an API such as Letermovir due to, for example, increased storage temperature, storage relative humidity, and increased storage duration.

Accordingly, according to the present invention, Letermovir is isolated from solution in an organic solvent in sufficient yield with sufficient purity and Letermovir remains stabilized in its amorphous state and retains its physicochemical characteristics so that the drug can then be prepared in the form of a tablet/capsule for oral administration, in which provides satisfactory dissolution characteristics, i.e. the degree of dissolution of amorphous Letermovir is > 50% no later than after 30 minutes.

In accordance with the present invention, at the final stage of chemical synthesis, Letermovir is obtained by saponification of the corresponding methyl ester, which is used to separate both enantiomers by crystallization using (2S,3S)-(+)-di-O-4-toluoyl-Dtartaric acid. The chiral acid is removed by extraction with aqueous bicarbonate from the methyl tert-butyl ether (hereinafter referred to as MTBE) solution and the Letermovir methyl ester is saponified using aqueous sodium hydroxide in a two-phase system.

After saponification, the zwitterionic form of the compound can be extracted with MTBE at neutral pH. Finally, the solvent is replaced with acetone and amorphous API. Letermovir can be distinguished:

i) using a roller dryer or ii) using precipitation by adding, with stirring, a solution of amorphous API-Letermovir in acetone or acetonitrile to excess water and subsequent drying at an elevated temperature of 40-80° C. in a conical dryer.

Alternatively, precipitation can be accelerated by adding water, as an antisolvent, to a solution of amorphous API-Letermovir in acetonitrile or acetone. This method results in a sticky substance that must be further processed to produce a solid amorphous API-Letermovir, which can be isolated by filtration.

Thanks to the above isolation techniques, Letermovir can be isolated in an amorphous state at chemical and chiral purity that is within acceptable limits for residual solvents, and it has physicochemical characteristics that are suitable for the preparation of galenic preparations without the need for additional steps such as grinding or micronization.

The indicated physicochemical characteristics mean that the specific surface area of the amorphous Letermovir obtained in accordance with the present invention is equal to at least 1 m ² /g, if the specific surface area (SSA) of the isolated Letermovir is determined by the Brunauer-Emmett-Teller method using following typical conditions:

Principle: nitrogen adsorption at 77 K; Brunauer, Emmett and Teller technique (BET)

Method: volumetric method (method II) according to USP (United States Pharmacopoeia) <846>

Device: Tristar 3000/VacPrep 061 (Micromeritics)

Sample weight: approximately 1.5-2.5 g

Sample preparation: degassing in vacuum at 40°C for 2 hours (final vacuum < 2.7 Pa)

Pressure range p/p ₀ : 0.05-0.15 (3 experimental values).

These physicochemical characteristics also mean that the mean particle size distribution (PSD) is no more than 10 µm when the particle size distribution of the isolated Letermovir of the present invention is determined using the following typical conditions:

Device: Mastersizer 2000 using dry dispersion

Methodology: according to Fraunhofer; weighed quantity: 0.3-0.4 g

Measurement duration: 20 s

Background time: 6s

Sensitivity reduction limits: 0.5 to 6%

Sample cell: microvolume; fine sieve with balls

Loading speed: 45-55%

Dispersing pressure: 2.5 bar.

It is necessary to conduct four independent studies and average the results.

These physicochemical characteristics also mean that Letermovir, proposed in the present invention, contains a pharmaceutically acceptable amount of toxic impurities, namely:

i) the mesityl oxide impurity content is </= 31 ppm when determined by static gas chromatography headspace analysis technique as detailed in the specific embodiment (12) below, and/or ii ) the 3-methoxyaniline impurity content is <20 ppm, preferably <15 ppm, more preferably <10 ppm, even more preferably <5 ppm, most preferably <1.5 ppm ppm if determined using gas chromatography under the following experimental conditions:

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Device gas chromatograph, for example Agilent 6890 Column DB-1, length 60 m, inner diameter 0.25 mm, film thickness 1 µm Carrier gas, flow rate nitrogen, 1.7 ml/min, constant flow rate Sample division factor 1:5 Injector temperature 150°C Oven temperature program Initial temperature 70°C Holding time 5 minutes 1. Heating speed 8 K/min 1. Final temperature 120°С Holding time 22 min 2. Heating speed 25 K/min 2. Final temperature 300°C Holding time 2 minutes Duration of analysis 42.45 min Injected volume 5 µl FID (flame ionization detector): Temperature 300°C Flammable gases hydrogen: 40 ml/min; air: 450 ml/min Make-up gas (N ₂ ) 25 ml/min Purging Carrier gas, flow rate nitrogen: 2.5 ml/min, constant flow rate Sample division factor 1:5 Injector temperature 300°C Oven temperature program Initial temperature 300°C Holding time 15 minutes Duration of analysis 15 minutes Injected volume 5 µl

One skilled in the art will appreciate that the specific surface area of a powdered substance, such as amorphous Letermovir, increases as particle size decreases. Accordingly, the area of the active pharmaceutical ingredient, Letermovir, increases, which improves its dissolution and absorption profile when administered orally in the form of solid oral dosage forms.

According to the present invention, it has surprisingly been found that using the above-described isolation method, it is possible to obtain powdered amorphous Letermovir having an average particle size distribution of not more than 10 μm and/or a specific surface area of not less than 1 m ² /g. In addition, the amorphous Letermovir obtained by the method proposed in the present invention has high purity, which makes it pharmaceutically acceptable and ready for inclusion in solid dosage forms for oral administration.

The authors of the present invention have developed galenic preparations containing isolated Letermovir in an amorphous state, in which it is maintained in an amorphous state without affecting its pharmaceutical activity and dissolution characteristics.

The inventors of the present invention have also unexpectedly developed chemically stable galenic preparations containing amorphous Letermovir, in which the degree of dissolution of the amorphous Letermovir contained in the granulated preparation is >50% no later than 30 minutes.

In addition, the present inventors have unexpectedly developed solid pharmaceutical preparations containing amorphous Letermovir, which provide an absolute bioavailability (F) of 30 to 95%, preferably 50 to 95%, more preferably 60 to 95%.

Thus, the present invention combines the advantages of using Letermovir, which is in a metastable amorphous state, i.e. having improved dissolution characteristics, with the advantages of corresponding herbal preparations ensuring its maintenance in an amorphous state, thereby obtaining orally administered solid dosage forms such as tablets or capsules. In addition, the present invention takes advantage of the lipophilicity of Letermovir in the amorphous state to obtain Letermovir-containing solid pharmaceutical preparations that provide an absolute bioavailability (F) of the amorphous Letermovir API contained in the granulated preparation of >30% , preferably > 40%, more preferably > 50%, even more preferably >

70%, even more preferably >80% and most preferably >90%.

As is known to one skilled in the art, in addition to improving the dissolution characteristics, the lipophilicity of Letermovir in the amorphous state, which is maintained by the isolation methods and processing methods of the present invention, also improves the bioavailability characteristics of the amorphous Letermovir API.

In addition, it is generally known that the amorphous state is a metastable state and this leads to the emergence of a thermodynamic driving force for crystallization. In cases where a predominantly crystalline drug is converted into an amorphous state to improve solubility and dissolution characteristics, it is common to prepare, for example, a solid dispersion (or melt extrusion) of the drug using pharmaceutically acceptable polymers to stabilize the drug-polymer complex and prevent crystallization

Thanks to the above-described isolation method, long-term stable solid pharmaceutical preparations containing amorphous Letermovir are obtained without processing it by obtaining a solid dispersion or by performing melt extrusion. In this regard, one skilled in the art knows that isolating amorphous Letermovir with high quality is not an easy task.

Isolation of Letermovir using a roller dryer

The present inventors have found that the roller drying method is suitable for isolating Letermovir.

This method begins as follows:

use a solution of Letermovir in acetone, applied in the form of a very thin film on a heated rotating drum (40-60°C, preferably 60°C), which is placed in a vacuum chamber, the pressure of which is approximately 200 mbar, then Letermovir is removed from the drum using scraper

This method has limitations on the working capacity and produces Letermovir in an amorphous state, which must be subjected to a final drying procedure in order for the residual solvent content to meet ICH (International Conference on Harmonization) requirements.

Isolation of Letermovir by precipitation from acetonitrile or acetone by addition to excess water

In addition, the authors of the present invention have found that Letermovir can be isolated in an amorphous state if it is precipitated from acetonitrile or acetone by adding to excess water.

This precipitation method, intended for the isolation of amorphous Letermovir, is carried out from water-miscible solvents, acetonitrile or acetone, by adding excess water with stirring. Isolation is then carried out by filtration or centrifugation. An optional vacuum drying step is then carried out.

In accordance with the above, the present inventors have found that precipitation, filtration and vacuum drying at elevated temperatures of 40-80° C. are suitable for isolating amorphous Letermovir having excellent purity and suitable physicochemical characteristics, in particular particle size distribution and specific surface area, which then allows it to be incorporated into a tablet.

Effect of solvents on the release of Letermovir

In addition, the present inventors have discovered that the release of Letermovir generally occurs in a solvent-dependent manner and therefore specific and suitable solvents are required to obtain Letermovir in a pure and chemically stable amorphous state.

During chemical studies and selection of optimal conditions for obtaining amorphous Letermovir, which has pharmaceutical purity, the following water-miscible solvents were studied: ethanol, tetrahydrofuran (THF), methyl ethyl ketone (MEK, 2-butanone), methanol and acetonitrile.

The present inventors have found that ethanol, THF and MEK are not suitable for use as solvents to obtain pharmaceutical grade amorphous Letermovir, either due to insufficient quality of the product (impurities, residual solvents) or due to the precipitation procedure and precipitation itself.

Therefore, ethanol, THF and MEK were preferably not used for precipitation, and the precipitation of Letermovir was carried out from an organic solution, preferably from a solution in acetone.

The present inventors have found that methanol is unsuitable for isolating Letermovir and obtaining an amorphous API of pharmaceutical grade, since when harsh conditions are used, possible side reactions such as transesterification may occur, which imposes limitations on carrying out this isolation method in an industrial scale. scale.

In contrast, the present inventors have surprisingly found that only acetonitrile and acetone provide sufficient precipitation and production of Letermovir in an amorphous state at pharmaceutical grade. The Letermovir thus obtained has sufficient purity with sufficient yield as well as suitable physico-chemical characteristics and thus can be directly used for the preparation of herbal preparations which can be used for the preparation of orally administered tablets/capsules by granulation.

Therefore, acetonitrile and acetone according to the present invention are the preferred water-miscible solvents used to precipitate amorphous Letermovir. Taking into account the residual solvent limits specified in the current ICH guidelines, acetone is even more preferable as it is a low toxicity solvent.

Thus, acetone is the most preferred organic solvent used to precipitate amorphous Letermovir.

In addition, residual solvents (acetonitrile, acetone, water) can be effectively removed under vacuum at elevated temperatures (40-80°C) without compromising purity or changing physicochemical characteristics such as amorphous state, particle size distribution and specific surface area.

Isolated amorphous Letermovir contains less than 5000 ppm acetone (meeting ICH guidelines) and <2% water content (internal limit).

Manufacturing of tablets/capsules

Processing methods based on dry granulation and wet granulation (also known as high shear granulation or top spray granulation) are described to produce IR film-coated tablets/capsules containing isolated Letermovir in an amorphous state at different doses. In addition, the present inventors have developed dry granulation methods for producing IR film-coated tablets containing isolated Letermovir in an amorphous state at different doses.

The dry granulation process can be carried out using a tablet press (aggregation) or using a roller press.

Therefore, preparations obtained by dry granulation are provided containing the isolated Letermovir in an amorphous state, which can be obtained using a tablet press or using a roller press.

Another major difficulty encountered when using Letermovir, isolated in the form of an amorphous API, which must be further processed by granulation, is the drying procedure itself.

If the surface of the amorphous agent, Letermovir, dries out, a surrounding layer is formed that interferes with subsequent drying. This behavior of an amorphous API intended for oral pharmaceutical preparations does not allow conventional drying techniques used in the pharmaceutical industry and, in addition, imposes inevitable limitations on industrial scale production.

To carry out dry and wet granulation of Letermovir in the amorphous state, polymers are used as binders, which are hydrophilic in nature and thus have a beneficial effect on the dissolution characteristics of Letermovir, since it is a hydrophobic but lipophilic solid.

Therefore, polymers selected from the group consisting of, but not limited to, hydroxypropyl methylcellulose (also known as hypromellose or HPMC), povidone (also known as polyvinylpyrrolidone, polyvidone or PVP), starch (including pregelatinized starch) are used as binders in the preparations obtained by granulation according to the present invention.

Granulation method/wet and dry granulation

The present inventors discovered that in the case of wet granulation, after mixing the amorphous Letermovir solid with ethanol, the resulting product was extremely wet and the results were not reproducible, regardless of the ethanol content.

Therefore, alcohols, in particular methanol and ethanol, were not used as technological additives for wet granulation of Letermovir in the amorphous state.

Therefore, acetone was not used as a processing aid for wet granulation of Letermovir in the amorphous state.

Thus, preferably, mixtures of ethanol and acetone were also not used as processing aids for wet granulation of Letermovir in the amorphous state.

- 9 043692

To overcome the above difficulties, the present inventors have discovered that replacing organic solvents with purified water results in an improved wet granulation processing aid for isolated amorphous Letermovir.

Thus, purified water is a technological additive suitable for wet granulation of Letermovir in an amorphous state.

The present inventors have also discovered that amorphous Letermovir isolated by roller drying can be processed by wet granulation.

However, from a technical point of view, dry granulation of the isolated amorphous Letermovir is preferable, since no additional drying is required, which may also affect the physicochemical characteristics and stability of Letermovir.

Therefore, API-Letermovir in an amorphous state obtained by precipitation is preferred for the subsequent processing proposed in the present invention.

In particular, the inventors of the present invention have discovered that precipitated Letermovir has favorable characteristics for obtaining homogeneous mixtures containing it during the drying procedure and subsequent compression in the manufacture of tablets.

Therefore, pharmaceutical preparations obtained by dry granulation contain precipitated Letermovir.

Galenic preparations containing roller-dried and precipitated Letermovir

It is known to one skilled in the art that the method of isolating amorphous compounds influences subsequent tabletting characteristics during manufacture.

In the description below, some parameters may differ slightly from the parameters of the solid pharmaceutical preparations described in the present invention. However, such differences are known to one skilled in the art. Thus, one skilled in the art will understand that the following objects are only preferred objects; however, the present invention should not be limited to such specific objects.

In addition to the isolated Letermovir, which is in an amorphous state, the solid pharmaceutical preparations of the present invention contain one or more pharmaceutically acceptable ingredients called excipients. Common excipients include, but are not limited to, fillers, diluents, binders, lubricants, glidants, disintegrants, solvents, film formers, plasticizers, pigments and antioxidants. All excipients that are part of the present invention are substances of synthetic or plant origin and are not derived from animals or humans.

All of the listed excipients that can be used to prepare the solid pharmaceutical preparations of the present invention containing the amorphous API Letermovir are well known and widely used for the manufacture of pharmaceutical dosage forms (for example, compressed tablets or capsules) using conventional pharmaceutical techniques, including granulation and compression. .

The solid pharmaceutical preparations of the present invention contain one or more excipients selected from the group consisting of microcrystalline cellulose, copovidone, croscarmellose sodium, colloidal anhydrous silicon dioxide, magnesium stearate, povidone (also known as polyvinylpyrrolidone, polyvidone or PVP ), lactose, sucrose, mannitol, starch (including pregelatinized starch), talc, hydroxypropylcellulose, hydroxypropylmethylcellulose (also known as hypromellose or HPMC), sodium starch glycolate, calcium hydrogen phosphate dihydrate (also known as calcium hydrogen phosphate), triethyl citrate, methacrylic acid - methyl methacrylate copolymers, polyvinyl alcohol, magnesium stearate, macrogol, poly(vinyl alcohol) graft copolymer, polyvinyl acetate, methacrylic acid/ethyl acrylate copolymers, or a combination thereof.

Preferably, solid pharmaceutical preparations contain as API Letermovir in an amorphous state in an amount from 20.0 to 70.0% (wt./wt.), povidone in an amount from 1.0 to 30.0% (wt./wt.) ), croscarmellose sodium salt in an amount from 1.0 to 30.0% (wt./wt.), microcrystalline cellulose in an amount from 10.0 to 90.0% (wt./wt.), colloidal anhydrous silicon dioxide in in an amount from 0.1 to 10.0% (w/w), and magnesium stearate in an amount from 0.01 to 10.0% (w/w).

Particularly preferably, the solid pharmaceutical preparations contain as an API Letermovir in an amorphous state in an amount of from 30.0 to 50.0% (w/w), povidone in an amount from 2.0 to 10.0% (w/w). .), croscarmellose sodium salt in an amount from 2.0 to 10.0% (wt./wt.), microcrystalline cellulose in an amount from 20.0 to 70.0% (wt./wt.), colloidal anhydrous silicon dioxide in an amount from 0.5 to 5.0% (w/w), and magnesium stearate in an amount from 0.1 to 5.0% (w/w).

In addition, solid pharmaceutical preparations containing Letermovir in an amorphous state can be prepared by granulation, preferably by wet granulation.

Also, solid pharmaceutical preparations containing Letermovir in an amorphous state,

- 10 043692 can be produced by roller compaction/dry granulation.

Solid pharmaceutical preparations containing Letermovir in an amorphous state can also be obtained by direct compression.

Precipitated amorphous Letermovir processed by dry granulation is a preferred embodiment of the present invention.

In particular, the present inventors have discovered that it is possible to perform granulation using a purified water/povidone solution.

The corresponding dissolution study results showed that the dissolution rate of Letermovir was >50% after no later than 30 minutes.

Therefore, a solid pharmaceutical preparation containing Letermovir in an amorphous state can be obtained by drying in a roller dryer and further processed with a mixture of purified water/povidone used as a processing aid for wet granulation, characterized by a dissolution rate of >50% no later than after 30 minutes, preferably >60% no later than 30 minutes, more preferably >70% no later than 30 minutes, even more preferably >80% no later than 30 minutes, most preferably >90% no later , than in 30 minutes.

A solid pharmaceutical preparation containing Letermovir in an amorphous state can be obtained by precipitation and further processed with a mixture of purified water/povidone used as a processing aid for wet granulation, characterized by a degree of dissolution of >50% no later than 30 minutes , preferably >60% no later than 30 minutes, more preferably >70% no later than 30 minutes, even more preferably >80% no later than 30 minutes, most preferably >90% no later than 30 min.

In addition, the present inventors have discovered that the dissolution of solid pharmaceutical preparations containing precipitated Letermovir in an amorphous state, which is further processed by dry granulation, is improved by the addition of disintegrants.

In particular, increasing the amount of croscarmellose sodium salt used as a disintegrant from the usual amount of 3% to 5% improves the dissolution of the amorphous Letermovir contained in the experimental oral tablet formulation and thus provides a dissolution rate of >50% no later than 30 minutes, preferably >60% no later than 30 minutes, more preferably >70% no later than 30 minutes, even more preferably >80% no later than 30 minutes, most preferably >90% no later than 30 min.

Thus, solid pharmaceutical preparations containing amorphous Letermovir, which contain croscarmellose sodium salt in an amount of at least 4%, preferably at least 5% in terms of the solid pharmaceutical preparation, are characterized by a degree of dissolution of >50% no later than 30 minutes , preferably >60% no later than 30 minutes, more preferably >70% no later than 30 minutes, even more preferably >80% no later than 30 minutes, most preferably >90% no later than 30 min.

Accordingly, to ensure the appropriate characteristics of herbal preparations known to one skilled in the art, the amount of microcrystalline cellulose used as filler/binder must be reduced to compensate for the increase in the amount of croscarmellose sodium salt.

The solid pharmaceutical preparations proposed in the present invention contain Letermovir in an amorphous state in an amount of at least 5%, preferably at least 15%, more preferably at least 30%, even more preferably at least 40%.

The present inventors have found that generally amorphous Letermovir isolated by roller drying is more suitable for wet granulation processing, and amorphous Letermovir isolated by precipitation is more suitable for dry granulation processing.

The isolated amorphous Letermovir is contained in solid pharmaceutical preparations for oral administration in an amount of from 20 to 500 mg, preferably in an amount from 120 to 280 mg, most preferably in an amount of 240 or more than 240 mg.

In addition, isolated amorphous Letermovir is contained in solid pharmaceutical preparations for oral administration in an amount of 20 to 400 mg, preferably in an amount of 120 to 280 mg, most preferably in an amount of 240 or more than 240 mg.

Film-coated tablets containing amorphous Letermovir at different doses contain 5 or 20 mg, or 30 mg, or 60 mg, or 120 mg, or 240 mg Letermovir, or > 240 mg Letermovir. The individual dose values indicated should not be considered as limiting dose values. Any other dose that is reasonable to administer to a subject is also within the scope of the present invention.

- 11 043692

Dissolution Research Methodology

Throughout the present description, the corresponding dissolution test results are obtained based on the dissolution study using the Ph.Eur method. 2.9.3, Apparatus 2, at a blade rotation speed of 50 rpm, at 37.0 ± 0.5 ° C in 1000 ml of 0.1 N medium. HCl/0.2% sodium lauryl sulfate solution and examined by reverse phase HPLC at time intervals of 15, 30 and 45 minutes as follows:

HPLC conditions:

Column: Waters Symmetry Nucleosil 100 C18, 40 mmx4.0 mm, 10 µm

Detection wavelength: 256 nm

Approximate 4 min experiment duration:

The approximate time 1.3 min holding: Column temperature: 40°С Injected volume 20 µl Flow rate: 1.5 ml/min Mobile phase: buffer pH 4.0/acetonitrile; 55/45 rpm

Long-term stability

Galenic preparations for oral administration with long-term stability containing amorphous Letermovir are described. The precipitated amorphous Letermovir included in galenic preparations is physically and chemically stable when stored at 25°C and 60% relative humidity for at least 36 months.

Therefore, the amorphous Letermovir included in the herbal preparations of the present invention is physically and chemically stable when stored for at least 36 months at 25° C. and 60% relative humidity.

Oral administration intended for use in methods of treating viral infections

The herbal preparations proposed in the present invention containing amorphous Letermovir are intended for the preparation of medicinal products for oral administration to a subject intended for the prevention or treatment of viral infections. The specific indications for use of the solid pharmaceutical preparations of the present invention containing the amorphous API-Letermovir are selected from the group consisting of HCMV infections in a subject, preferably HCMV infections in a subject suffering from acquired immunodeficiency syndrome (AIDS), HCMV pneumonitis, HCMV encephalitis, as well as gastrointestinal and systemic HCMV infection, HCMV infection in neonates and children, acute HCMV infection in pregnant women, HCMV infection in immunocompromised cancer patients, and HCMV-infected cancer patients to suppress HCMV-mediated tumor progression (see J. Cinatl, et al, FEMS Microbiology Reviews 2004, 28, 59-77).

The herbal preparations proposed in the present invention containing the amorphous API Letermovir are intended for the preparation of medicinal products for oral administration to a subject intended for the prevention or treatment of diseases caused by viruses of the Herpesviridae family.

The herbal preparations of the present invention containing the amorphous API Letermovir are intended for use in combination with other antiviral active ingredients, such as Valganciclovir, Ganciclovir, Valacyclovir, Acyclovir, Foscarnet, Cidofovir and derivatives thereof, in a method of treating viral infections, preferably HCMV infections.

The herbal preparations proposed in the present invention, containing the amorphous API Letermovir, are intended for the prevention or treatment of viral infections. The specific indications for said use of the inventive solid pharmaceutical preparations containing the amorphous API-Letermovir are selected from the group consisting of HCMV infections in a subject, preferably HCMV infections in a subject suffering from AIDS, HCMV pneumonitis, HCMV encephalitis, and gastrointestinal tract. enteric and systemic HCMV infection, HCMV infections in neonates and children, acute HCMV infection in pregnant women, HCMV infection in immunocompromised cancer patients, HCMV-infected cancer patients to suppress HCMV-mediated tumor progression (see J. Cinatl , et al., FEMS Microbiology Reviews 2004, 28, 59-77).

Another embodiment of the present invention is the use of the herbal preparations proposed in the present invention containing amorphous API-Letermovir for the prevention or treatment of diseases caused by viruses of the Herpesviridae family.

In the context of the above description, particularly preferred embodiments of the present invention are defined by the following numbered and related embodiments:

(1) Powdered Letermovir of formula (I)

Formula (I), which is in an amorphous state and is suitable for use in solid dosage forms for oral administration, wherein said Letermovir is characterized in that:

i) according to a BET (Brunauer-Emmett-Teller) specific surface area study, it has a specific surface area of at least 1 m ² /g, and/or ii) according to a particle size distribution study, it has an average particle size distribution sizes not exceeding 10 microns, which is obtained by a precipitation method involving the preparation of a solution of letermovir in water-miscible solvents selected from acetone or acetonitrile, and the precipitation of said letermovir from the solution while stirring in excess water, used as an antisolvent, followed by filtration or by centrifugation to obtain said powdered amorphous Letermovir.

(2) A solid pharmaceutical preparation for oral administration containing powdered Letermovir in an amorphous state and one or more pharmaceutically acceptable excipients.

(3) The solid pharmaceutical preparation according to embodiment (2), which is effective in providing an absolute bioavailability of Letermovir of 70 ± 30% when administered orally in the formulation containing at least 5 mg of Letermovir in an amorphous state.

(4) The solid pharmaceutical preparation according to embodiment (3), which is effective in providing an absolute bioavailability of Letermovir of 70 ± 30% when administered orally in the formulation containing > 240 mg of Letermovir in an amorphous state.

(5) The solid pharmaceutical preparation according to embodiment (3) or (4), further comprising povidone, croscarmellose sodium, microcrystalline cellulose, colloidal anhydrous silica and magnesium stearate.

(6) The solid pharmaceutical preparation according to embodiment (5), wherein said Letermovir in an amorphous state is contained in an amount of from 30.0 to 50.0% (w/w), said povidone is contained in an amount from 2.0 to 10.0% (w/w), said croscarmellose sodium salt is contained in an amount from 2.0 to 10.0% (w/w), said microcrystalline cellulose is contained in an amount from 20.0 to 70.0 % (w/w), said colloidal anhydrous silica is contained in an amount of from 0.5 to 5.0% (w/w) and said magnesium stearate is contained in an amount of from 0.1 to 5.0% ( w/w).

(7) The solid pharmaceutical preparation according to embodiment (5) or (6), containing croscarmellose sodium salt as a disintegrant in an amount of not less than 4.0% (w/w).

(8) The solid pharmaceutical preparation according to embodiment (7), containing croscarmellose sodium salt as a disintegrant in an amount of not less than 5.0% (w/w).

(9) The solid pharmaceutical preparation according to any one of embodiments (2) to (8), wherein the arginine solution, in particular the L-arginine solution, is not contained in the pharmaceutical preparation.

(10) A solid pharmaceutical preparation according to any one of embodiments (2)-(9), in which Letermovir in an amorphous state is contained at a dose of 5 or 20 mg, or 30 mg, or 60 mg, or 120 mg, or 240 mg, or > 240 mg.

(11) The solid pharmaceutical preparation according to any one of embodiments (2) to (10), wherein Letermovir in the amorphous state has a dissolution rate of >50% no later than 30 minutes, preferably >60% no later than 30 minutes , more preferably > 70% no later than 30 min, even more preferably > 80% no later than 30 min, most preferably > 90% no later than 30 min if the dissolution of Letermovir in the amorphous state is studied using method Ph.Eur.

- 13 043692

2.9.3, Apparatus 2, at a blade rotation speed of 50 rpm, at 37.0±0.5°C in 1000 ml of medium

0.1 n. HCl/0.2% sodium lauryl sulfate solution and examined by reverse phase HPLC for 30 minutes as follows.

HPLC conditions:

Column: Waters Symmetry Nucleosil 100 C18, 40 mmx4.0 mm, 10 microns Detection wavelength: 256 nm Approximate Experiment Duration: Approximate Retention Time: 4 min 1.3 min Column temperature: 40°С Injected volume Flow rate: Mobile phase: 20 µl 1.5 ml/min pH 4.0 buffer/acetonitrile; 55/45 rev/rev

(12) The solid pharmaceutical preparation according to any one of embodiments (2)-(11), wherein said solid pharmaceutical preparation is an immediate release preparation, characterized in that at least 85% of Letermovir in the amorphous state dissolves no later than 30 minutes at using USP Apparatus I at 100 rpm or USP Apparatus II at 50 rpm in each of the following media of 900 mL or less:

(1) an acidic environment such as enzyme-free artificial gastric juice USP;

(2) a buffer having a pH value of 4.5; and (3) a buffer having a pH value of 6.8 or enzyme-free artificial gastric juice USP.

(13) The solid pharmaceutical preparation according to any one of embodiments (2) to (12), wherein said Letermovir in an amorphous state is chemically stable for at least 36 months when stored at room temperature (25°C) and relative humidity ( 60%) if determined by reverse phase HPLC using a gradient mode as follows:

HPLC conditions:

Column:

Solvent:

Eluent:

Detection wavelength:

Column temperature:

Injected volume:

Flow rate:

Duration of the experiment:

Intertsil ODS III, 5 µm, or equivalent acetonitrile/0.1 N. HC1 solution; 3+7 (v/v) A: water, pH 2.40; B: acetonitrile 235 nm

40°C µl 1.0 ml/min 30 min (14) A solid pharmaceutical preparation according to any one of embodiments (2)-(13), intended for use in the prevention or treatment of diseases associated with viruses of the Herpesviridae family, preferably associated with cytomegalovirus (CMV), even more preferably related to human cytomegalovirus (HCMV).

(15) The solid pharmaceutical preparation according to embodiment (14) for use in the prevention or treatment of diseases selected from the group consisting of HCMV infections in a subject, preferably HCMV infections in a subject suffering from AIDS, HCMV pneumonitis, HCMV encephalitis, and also gastrointestinal and systemic HCMV infection, HCMV infection in neonates and children, acute HCMV infection in pregnant women, HCMV infection in immunocompromised cancer patients, HCMV-infected cancer patients to suppress HCMV-mediated tumor progression.

Letermovir in the amorphous state of the present invention also has long-term stability in that, without solid dispersion or melt extrusion treatment, it remains in the amorphous state for at least 36 months when stored at 25° C. and relative humidity , equal to 60%.

In the context of the present invention, volatile solvents are selected from the group consisting of methanol, ethanol, acetonitrile, dichloromethane and MTBE.

In the context of the present invention, the antisolvent is water.

In the context of the present invention, the organic solvent is selected from the group consisting of acetonitrile and acetone.

- 14 043692

Definitions

In the context of the present invention, the term amorphous when used in relation to solid Letermovir means such a characteristic that there is no long-range order in the arrangement of neighboring molecular units, whereas its crystalline analogues have a strictly defined long-range order. Thus, amorphous Letermovir has two characteristics; a) the mechanical, thermal, electrical and chemical characteristics of Letermovir do not depend on the direction in which the substance is studied (isotropy), and b) with increasing temperature, Letermovir softens and turns into a liquid state only gradually, this means that the substance in the amorphous state does not have an exact value melting temperature.

Accordingly, Letermovir is in an amorphous state if it does not have a detectable crystalline content/signal when examined using an appropriate crystallographic technique.

Accordingly, throughout the present specification, in the context of the present invention, the expressions amorphous, amorphous form, amorphous state mean a material in which, using standard XRPD techniques, no evidence of crystallinity corresponding to exceeding the detection limit of 2% is detected, and thus does not have detectable crystal content/signal when examined using appropriate crystallographic techniques. X-ray powder diffraction (XRPD) is typically used to determine the crystalline portion of the material of the present invention. Three typical analysis techniques are described below, but are not limiting:

a) The sample is prepared on a rotating sample holder having an effective surface area of 1.9 mm (diameter). X-ray powder diffraction patterns were collected using a Bruker D8 Advance powder diffractometer equipped with a LynxEye PSD detector and Ni β filter using CuKa radiation operating at 40 kV and 30 mA. Measurements are carried out in steps of 0.06° with a step duration of 0.5 s.

b) Use a Siemens D5000 powder diffractometer equipped with a secondary graphite monochromator, using CuKa radiation, operating at 40 kV and 30 mA. The effective surface area is 6x10 mm. Measurements are carried out in steps of 0.02° with a step duration of 2 s.

c) Use a Seifert DX-Cu8*0.4-S X-ray tube equipped with a 616.2 germanium (111) monochromator and an imaging device, a Guinier G670 powder X-ray camera manufactured by Huber, using CuKa radiation, operating at 40 kV and 30 mA, in the scanning range 0° < 2Θ < 100° and with a step width Δ (2Θ) = 0.005°.

Isotropy of characteristics is also a feature of a substance in a polycrystalline state. However, the substance in this state is characterized by a strictly defined melting point, and this fact makes it possible to distinguish it from Letermovir in the amorphous state. Differences in structures corresponding to the amorphous and crystalline states can be easily detected in x-ray diffraction patterns obtained, for example, using the XRPD techniques described above. Monochromatic X-rays are scattered by crystals and a diffraction pattern is formed containing individual peaks that are not characteristic of the amorphous state.

As stated above, the characteristics of amorphous Letermovir are a consequence of the lack of long-range order. In contrast, long-range order is present in crystals that have strict periodicity of the same structural element, i.e. an atom, a group of atoms, a molecule, etc., in all directions over hundreds and thousands of periods. At the same time, Letermovir in the amorphous state has short-range order.

In the context of the present invention, short-range order means the regular arrangement of neighboring Letermovir particles, i.e. order is observed at distances comparable to the size of molecules if the Letermovir core is studied using an electric field gradient on the probe. As the distance increases, this order deteriorates and disappears at a distance of 0.5-1 nm. Short-range order is also characteristic of liquids, but in the case of liquids there is a frequent exchange of positions of neighboring particles; however, this exchange occurs less frequently as Letermovir's viscosity increases. The viscosity of Letermovir according to the present invention can be determined using viscometers and/or rheometers known to one skilled in the art.

The expressions zwitterionic, zwitterionic characteristics and zwitterionic in the context of the present invention when used in relation to API-Letermovir mean that the Letermovir molecule is a neutral molecule having a positive and negative electrical charge located in different positions of the same molecule. Accordingly, API Letermovir has a charge that varies with pH when measured in an electric field. Thus, Letermovir moves in an electric field and the direction of movement depends on the total charge that the molecules have. The total charge is affected by the pH value. Letermovir has a constant isoelectric point (pI), which is the pH value at which the number of cations is equal to the number of anions. At this point (pI = 5.55), the total electric charge of Letermovir is always zero.

The terms dissolution, dissolution characteristics, mean the phenomenon or property of a solid, liquid or gas forming a solution in a solvent. In the case of dissolution of solids, the phenomenon of dissolution can be explained as the breakdown of the crystal lattice into individual ions, atoms or molecules and their transfer into the solvent. For complete dissolution, the total free energy must be negative.

Throughout the present description, the expression sufficient dissolution when used in relation to the amorphous Letermovir proposed in the present invention means a degree of dissolution of > 50% no later than 30 minutes, preferably a degree of dissolution > 60% no later than 30 minutes, more preferably a degree dissolution > 70% no later than 30 min, even more preferably dissolution > 75% no later than 30 min, even more preferably dissolution > 80% no later than 30 min, even more preferably dissolution > 85% no later than 30 min, most preferably a degree of dissolution > 90% no later than 30 min if dissolution is tested using method Ph.Eur.2.9.3, Apparatus 2, with a blade speed of 50 rpm, at 37.0±0.5°C in 1000 ml of 0.1 N medium. HCl/0.2% sodium lauryl sulfate solution and examined by reverse phase HPLC at time intervals of 15, 30 and 45 minutes as follows:

HPLC conditions:

Column: Waters Symmetry Nucleosil 100 C18, 40 mmx4.0 mm, 10 µm

Detection wavelength: 256 nm

Approximately 4 min

duration of the experiment: The approximate time 1.3 min holding: Column temperature: 40°С Injected volume 20 µl Flow rate: 1.5 ml/min Mobile phase: pH 4.0 buffer/acetonitrile; 55/45 rpm

In contrast, solubility is a characteristic of the ability of a solid, liquid, or gaseous chemical to dissolve in a solid, liquid, or gaseous solvent to form a uniform solution of the solute in the solvent. The solubility of a substance depends significantly on the solvent used, as well as on temperature and pressure. The degree of solubility of a substance in a particular solvent is defined as the saturation concentration, when adding more solute does not increase the concentration of the solution. Solubility should not be confused with the ability to dissolve or liquefy a substance, since a solution can be formed not only due to dissolution, but also due to a chemical reaction. Solubility is also independent of particle size and other kinetic factors; given enough time, even large particles will eventually dissolve.

The term bioavailability generally means a subcategory of absorption and is the proportion of Letermovir from an administered dose that enters the systemic circulation; it is one of the main pharmacokinetic characteristics of drugs. By definition, when a drug is administered intravenously, its bioavailability is 100%. However, if the drug is administered by other routes (eg, orally), its bioavailability is usually reduced (due to incomplete absorption and first-pass metabolism) or may vary between individuals. Bioavailability is one of the essential characteristics in pharmacokinetics; bioavailability should be taken into account when calculating doses for non-intravenous routes of administration.

When used in relation to the API-amorphous Letermovir proposed in the present invention, the expression sufficient bioavailability means that the amorphous Letermovir contained in the solid pharmaceutical preparations proposed in the present invention has an absolute bioavailability (F) from 30 to 95%, preferably from 50 to 95%, more preferably 60 to 95% when administered in oral dosage forms. In other words, this expression also means that chemically stable, orally administered solid pharmaceutical preparations containing amorphous Letermovir or its pharmaceutically acceptable salts, solvates or hydrates are characterized in that the absolute bioavailability (F) of the amorphous Letermovir API contained in the resulting granulation preparation, is > 30%, preferably > 40%, more preferably > 50%, even more preferably > 70%, more

- 16 043692 more preferably >80% and most preferably >90%.

In the context of the present invention, the term immediate release tablet or IR generally means tablets and capsules that release the Letermovir API after a short period of time, typically less than 30 minutes. More specifically, the specified expression means such characteristics that at least 85% of the amount of the drug-Letermovir is dissolved no later than 30 minutes when using USP Apparatus I at 100 rpm or USP Apparatus II at 50 rpm in each of the specified below media volume 900 ml or less:

(1) an acidic environment such as enzyme-free artificial gastric juice USP;

(2) a buffer having a pH value of 4.5; and (3) a buffer having a pH value of 6.8 or enzyme-free artificial gastric juice USP.

In other cases, the product containing Letermovir is considered to be slowly soluble.

Accordingly, in the context of the present invention, the term extended or delayed release tablet formulation means tablets and capsules that release API-Letermovir at a reduced and controlled release rate over a specified period of time. Typically, extended-release tablets and capsules release their ingredient after 8, 12, 16, and 24 hours when tested using USP Apparatus I at 100 rpm or USP Apparatus II as described above.

An IR product, IR tablet/capsule dosage form is considered to be rapidly dissolving if at least 85% of the quantity of the specified drug dissolves within 30 minutes or less when using USP Apparatus I at 100 rpm or USP Apparatus II at 50 rpm in each of the following media in a volume of 900 ml or less:

(1) an acidic environment such as enzyme-free artificial gastric juice USP;

(2) a buffer having a pH value of 4.5; and (3) a buffer having a pH value of 6.8 or enzyme-free artificial gastric juice USP.

In other cases, the finished drug is considered to be slowly soluble.

The term pharmaceutical activity of Letermovir means antiviral activity against HCMV isolates obtained from the corresponding individual, within the EC ₅₀ ± SD (standard deviation) range of 0.0005-0.005 ± 0.0001-0.001.

The term chemically stable in the context of the present invention means that the purity of API-Letermovir contained in the solid pharmaceutical preparations of the present invention is at least 97.0%, preferably more than 97.0%, more preferably more than 98.0%, most preferably more 99.0%. Alternatively, chemically stable can also be characterized by the maximum amount of decomposed compound under normal storage conditions (5-40°C, 40-80% relative humidity), while the amount of impurities formed during the decomposition of the API is less than 3.0 wt.% in terms of per full weight of the API, if the specified drug is examined after a certain period of time using an appropriate HPLC technique, such as, for example:

Reverse phase HPLC gradient testing used for identification of finished drug product and determination of degradation products

Experiment conditions:

Column:

Solvent:

Eluent:

Detection wavelength: Column temperature:

Injected volume:

Flow rate:

Duration of the experiment:

Intertsil ODS III, 5 µm, or equivalent acetonitrile/0.1 and. HC1 solution; 3+7 (v/v) A: water, pH 2.40; B: acetonitrile 235 nm 40°C 15 µl 1.0 ml/min 30 min

The term physical stability in the context of the present invention means that there is no detectable content of crystalline moiety/signal related to the API when examined using an appropriate crystallographic technique and, furthermore, there is no significant change in particle size distribution and specific surface area.

The terms pure/purified when used in relation to the Letermovir API means that the API does not contain:

a) impurities resulting from decomposition, or by-products resulting from reagents or during the stages of the synthesis procedure,

b) residual solvents or water in quantities exceeding those present in the specified

- 17 043692 range, i.e. In the context of the present invention, the residual solvent contents correspond to those given in the current manual and the residual water content is <2%.

In addition, these terms mean that there is no residual MTBE. In addition, these terms mean that the mesityl oxide content does not exceed 800 ppm when determined by reverse phase gradient HPLC testing used for identification of the finished drug product and determination of degradation products

Experiment conditions:

Column: Solvent: Intertsil ODS III, 5 µm, or equivalent acetonitrile/0.1 N. HC1 solution; 3+7 (rev/rev) Eluent: A: water, pH 2.40; B: acetonitrile Detection wavelength: Column temperature: 235 nm 40°C Injected volume: 15 µl Flow rate: 1.0 ml/min

Experiment duration: 30 min

In this context, the expression pharmaceutically acceptable impurity content when used in relation to the isolated amorphous Letermovir proposed in the present invention means that the amorphous Letermovir thus obtained is characterized in that the content of mesityl oxide is </= 31 ppm, preferably </= 27 ppm, even more preferably </= 23 ppm, most preferably </= 10 ppm when determined by static gas chromatography headspace assay as described in detail in the above specific (12) embodiment, and/or the content of 3-methoxyaniline is <20 ppm, preferably <15 ppm, more preferably <10 ppm, even more preferably <5 ppm ppm, most preferably < 1.5 ppm when determined by gas chromatography under the following experimental conditions:

Device gas chromatograph, for example Agilent 6890 Column DB-1, length 60 m, inner diameter 0.25 mm, film thickness 1 µm Carrier gas, flow rate Sample split ratio nitrogen, 1.7 ml/min, constant flow rate 1:5 Injector temperature Oven temperature program 150°C Initial temperature 70°C Holding time 1. Heating speed 5 minutes 8 K/min 1. Final temperature 120°С Holding time 2. Heating speed 22 min 25 K/min 2. Final temperature 300°С Holding time 2 minutes Duration of analysis Injected volume FID: 42.45 min 5 µl

Temperature 300°С Flammable gases hydrogen: 40 ml/min; air: 450 ml/min Make-up gas (N2) 25 ml/min

Purging

Carrier gas, flow rate Sample split ratio Injector temperature Furnace temperature program nitrogen: 2.5 ml/min, constant flow rate 1:5 300°С Initial temperature 300°C Holding time Duration of analysis Injected volume 15 minutes 15 minutes 5 µl

and/or that there is no residual MTBE, and/or that the residual water content is <

- 18 043692

2%, and/or that the residual acetone content is less than 5000 ppm, and/or that the residual acetonitrile content is less than 410 ppm, if determined by the appropriate procedures specified above.

The term metastable, when used in relation to amorphous Letermovir, means a chemical state in a temporary energy trap or a somewhat stable intermediate state of a system that can lose energy in parts.

The term chiral purity, when used in relation to amorphous Letermovir, means that >99% of the Letermovir of the present invention is in a single enantiomeric form according to the R/S system when assayed by chiral HPLC.

Experiment conditions:

Column:

Mobile phase:

In isocratic mode: Detection wavelength:

Column temperature: Injection volume:

Flow rate:

Chiralpak AD-H, 5 µm; 250x4.6 mm mixture of 900 ml n-heptane, 100 ml 2-propanol and 10 ml diethylamine 50 min

UV detection at 260 nm, NR (bandwidth) +/- 4 nm

45°С µl

1.0 ml/min

The expression acceptable limits for residual solvents means amounts of residual solvents that are within the recommendations of the ICH guidelines.

The term residual solvents when used in relation to pharmaceuticals in the present invention is defined as volatile organic chemicals that are used in the preparation of medicinal substances or excipients, or which are formed in this case, or which are used in the manufacture of finished medicinal products, in the case of the present invention - medicinal products substances based on Letermovir.

Solvents are not completely removed during the practical implementation of production methods. Appropriate selection of solvents for drug synthesis, based on toxicologically acceptable limits, is critical in the preparation of pharmaceutical herbal preparations. Because residual solvents do not provide beneficial therapeutic effects, all residual solvents must be removed to such an extent that the product meets specifications, good manufacturing practices, or other quality-related requirements. Finished medicinal products must contain amounts of residual solvents that do not exceed acceptable safe values.

In the context of the present invention, the term maximum dose preferably means a dose of Letermovir equal to 240 to 480 mg.

In the context of the present invention, the term maximum dose means a dose of Letermovir equal to 240 to 360 mg.

In the context of the present invention, the expression long-term stability means that the purity of Letermovir is >99% for at least 24 months. when stored at 25 °C and 60% relative humidity when determined by HPLC.

In the context of the present invention, the expressions suitable physicochemical characteristics, physicochemical characteristics when used in relation to the amorphous Letermovir proposed in the present invention, mean the following characteristics:

electrostatic characteristics, particle size distribution and specific surface area that are suitable for the tableting procedure;

limited hygroscopicity, allowing processing under cooking conditions that do not require equipment designed to regulate humidity;

chemical stability during storage and processing conditions at 25 ° C and relative humidity equal to 60%;

no propensity for unregulated crystallization as determined by appropriate XRPD technique.

More specifically, the expressions suitable physicochemical characteristics, physicochemical characteristics mean that the specific surface area of amorphous Letermovir is equal to at least 1 m ² /g, if the specific surface area of the isolated Letermovir proposed in the present invention is determined by the BET method as indicated above, and/or that the average particle size distribution (D50 or d(0.5)) is not more than 10 μm, preferably not more than 9 μm, if the particle size distribution of the isolated Letermovir proposed in the present invention , are determined as above.

The expression suitable for use in solid oral dosage forms when used in relation to the amorphous Letermovir of the present invention means that the isolated amorphous Letermovir has a mean particle size distribution (PSD) of no more than 10 μm, preferably no more than 9 µm, and/or a specific surface area of at least 1 m ² /g, preferably at least 2 m ² /g. This expression also means that the amorphous Letermovir thus obtained by the isolation method proposed in the present invention has a pharmaceutically acceptable impurity content, which means that the amorphous Letermovir thus obtained is further characterized in that the content of mesityl oxide is </= 31 parts./ ppm, preferably </= 27 ppm, even more preferably </= 23 ppm, most preferably </= 10 ppm and/or 3methoxyaniline content < 20 ppm, preferably < 15 ppm ./million, more preferably < 10 ppm, even more preferably < 5 ppm, most preferably < 1.5 ppm, and/or that no residual MTBE is contained, and/or that the content residual water is <2%, and/or that the residual acetone content is less than 5000 ppm, and/or that the residual acetonitrile content is less than 410 ppm, if the content of these impurities is determined by the appropriate methods specified above .

In addition, the expression suitable for use in solid dosage forms for oral administration also means that the amorphous Letermovir thus obtained by the isolation method proposed in the present invention has satisfactory dissolution characteristics, which means that the amorphous Letermovir has a dissolution rate of > 50% without later than after 30 minutes, preferably a degree of dissolution > 60% no later than after 30 minutes, more preferably a degree of dissolution > 70% no later than after 30 minutes, even more preferably a degree of dissolution > 75% no later than 30 min, even more preferably a degree of dissolution > 80% no later than 30 min, even more preferably a degree of dissolution > 85% no later than 30 min, most preferably if amorphous Letermovir is characterized by a degree of dissolution > 90% no later than after 30 minutes, if its dissolution is examined using the method Ph.Eur.2.9.3, Apparatus 2, with a blade rotation speed of 50 rpm, at 37.0 ± 0.5 ° C in 1000 ml of medium 0.1 n. HCl/0.2% sodium lauryl sulfate solution and examined by reverse phase HPLC at time intervals of 15, 30 and 45 min as follows.

HPLC conditions:

Column: Waters Symmetry Nucleosil 100 C18, 40 mmx4.0 mm, 10 µm

Detection wavelength: 256 nm

Approximate 4 min experiment duration:

The approximate time 1.3 min

holding:

Column temperature: 40°C Injected volume 20 µl Flow rate: 1.5 ml/min Mobile phase: pH 4.0 buffer/acetonitrile; 55/45 rev/rev

In accordance with the above context, the expression suitable for use as orally administered pharmaceutical agents when used in relation to the amorphous Letermovir described above, which can be obtained in accordance with the present invention, means that the specified Letermovir used as an API is ready for direct inclusion in the herbal preparations of the present invention, and thus can be directly administered in solid oral dosage forms that are useful in methods of treating viral diseases, preferably cytomegalovirus (hereinafter referred to as HCMV) infections.

In the context of the present invention, the term pharmaceutical grade means the purity and stability of amorphous Letermovir, meeting the requirements of current international standards in accordance with the ICH, FDA (Federal Medicines Administration) and EMEA (European Agency for the Evaluation of Medicines).

In the context of the present invention, the term ICH guide means the publication of the International Conference on Harmonization of impurities: Guideline for residual solvents Q3C(R5). The purpose of this guideline is to recommend amounts of residual solvents in pharmaceutical preparations that are acceptable to ensure patient safety. The guideline recommends the use of less toxic solvents and describes the amounts of some residual solvents considered toxicologically acceptable. The guidance applies to all dosage forms and routes of administration. Higher levels of residual solvents may be acceptable in some cases, such as short-term (30 days or less) or local administration.

The term direct compression is used to define a procedure in which powdered mixtures of drug substance and excipients are directly compressed using a tableting machine. Apart from mixing, no mechanical processing of the powder is carried out. The most obvious advantage of direct pressing is its simplicity and the resulting cost-effectiveness.

In the context of the present invention, the drying or drying step can be carried out by drying using a cone dryer, a drum dryer or any other suitable technique known to a person skilled in the art.

In the context of the present invention, the expression particle size for a test particle means the diameter of an equivalent particle that is considered spherical and has the same light scattering pattern as the test particle. In the context of the present invention, the particle size is determined using laser diffraction. In particular, in the context of the present invention, a Mastersizer 2000, available from Malvern Instruments, is used to determine particle size.

In the context of the present invention, the D50 value or d(0.5) value of the particle size distribution describes a particle size such that 50 vol.% of the particles have a particle size smaller than the particle size that corresponds to the D50 value (d(0.5)) . This also means that 50 vol.% of the particles are larger than the corresponding D50 value (d(0.5)). Accordingly, the D90 value (d(0.9)) of the particle size distribution means that the particle size is such that 90 vol.% of the particles are smaller than the particle size corresponding to the D90 value (d(0.9)). Likewise, the D10 (d(0.1)) value of the particle size distribution means that the particle size is such that 10 vol.% of the particles are smaller than the particle size corresponding to the D10 (d(0.1)) value.

In the context of the present invention, the excipients used in solid pharmaceutical preparations have the purposes indicated in the table below. 1.

Table 1. Inert filler/purpose

Inert filler Purpose microcrystalline cellulose filler/binder colloidal anhydrous silica glidant agent polyvinylpyrrolidone polymer/binder croscarmellose sodium salt baking powder Magnesium stearate lubricant polyethylene glycol plasticizer hypromellose film-forming agent titanium oxide color pigment yellow iron oxide color pigment purified water processing aid

Abbreviations

Throughout this specification, the following abbreviations are used:

API stands for active pharmaceutical ingredient.

MTBE stands for methyl tertiary butyl ether, also known as methyl tertiary butyl ether, which is an organic compound with the molecular formula (CH ₃ ) ₃ COCH ₃ . MTBE is a volatile, flammable and colorless liquid that is poorly soluble in water.

DMF stands for dimethylformamide.

DMSO stands for dimethyl sulfoxide.

NMP stands for N-methyl-2-pyrrolidone.

MEK stands for methyl ethyl ketone.

THF stands for tetrahydrofuran.

XRPD stands for X-ray powder diffraction.

CMV stands for cytomegalovirus.

Ph.Eur. means the European Pharmacopoeia, which is a pharmacopoeia that lists a large number of active substances and excipients used in the preparation of pharmaceuticals in Europe. The monograph provides quality standards for all essential medicines used in Europe. All medicinal products sold in the 36 member countries of the European Pharmacopoeia must meet these quality standards so that consumers receive a guarantee for products obtained from pharmacies and other official suppliers.

Method Ph.Eur.2.9.3 means a procedure for studying the dissolution of solid dosage forms. The assay is used to determine the rate of dissolution of active ingredients contained in solid dosage forms (for example, tablets, capsules and suppositories).

Method Ph.Eur.2.5.12 means the semi-micro method for the determination of water content in accordance with 01/2005:20512 European Pharmacopoeia 5.0. The research methodology is used to determine the water content in API-Letermovir in the amorphous state.

IPC stands for Process Control.

SCDT means methyl{(4S)-8-fluoro-2-[4-(3-methoxyphenyl)niperazin-1-yl]-3-[2-methoxy-5(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4 -yl}acetate (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (1:1).

PSD stands for particle size distribution.

SSA stands for specific surface area.

BET stands for Brunauer-Emmett-Teller specific surface area technique.

Examples

1) A drug containing amorphous Letermovir with the addition of L-arginine

Preliminary studies were conducted on the composition of oral dosage forms containing amorphous Letermovir with the addition of L-arginine. The purpose of adding L-arginine to a preparation containing amorphous Letermovir was to increase the solubility and, thus, the bioavailability of the drug substance.

Several experimental batches of a preparation containing L-arginine obtained by granulation were prepared, as shown in table. 2.

Table 2. Preparations with the addition of L-arginine for dissolution studies

The consignment 1 2 3 4 5 Batch size (doses) 100 100 200 333 333 Ingredient A drug [mg/dose] Letermovir 120 120 120 120 120 L-Arginine 80 80 40 80 80 Hypromellose (Methocel E5 Premium LV) - - - 112.5 225 Water 1500 750 750 750 1500 Total (solids) 200 200 160 312.5 425

First, dissolution studies were carried out to identify a suitable method of preparation and composition of the granulation solution containing Letermovir. In the following experiments, the conditions for carrying out the granulation method with high shear force were investigated. Since this produced batches of tablets with a long disintegration time and slow release, we moved on to studying the fluidized bed granulation method. Unexpectedly, it turned out that this did not lead to an improvement in the solubility characteristics of the drug.

a) Results

The dissolution of Letermovir in the study of batches 1-3 containing L-arginine was not ideal due to insufficient wettability of the drug substance. Letermovir floated to the surface of the solution.

In addition, a slight foaming of the solution occurred and it became yellowish.

The dissolution times at pH 1.0 and 0.2% SDS (sodium dodecyl sulfate) for the three batches were respectively:

1) 22 min

2) 37 min

3) > 2 h (complete dissolution after 2 days), respectively.

After complete dissolution, the viscosity of solutions from batches 1-3 increased. For batches 4 and 5, no wettability problems occurred when Letermovir was dissolved in solutions containing L-arginine/hypromellose. Due to the high viscosity of the solution, Letermovir mixed with the solution without floating to the surface. Due to foaming and air entering the solution, it was not possible to determine the dissolution time of the drug substance in these batches. After keeping the solutions for 12 hours, clear (yellowish) solutions were obtained.

1b) Conclusion

A study of the solubility of the first three batches of drugs showed that Letermovir has insufficient wettability with water. In addition, the dissolution of Letermovir in water depends on the amount of L-arginine and (as expected) its concentration in water.

By increasing the viscosity of the aqueous solution with hypromellose, the difficulties associated with the wettability of Letermovir were overcome. The drug substance did not float to the surface of the solution and was immediately mixed with the solution. However, due to foaming and air entering the resulting solution, it is impossible to determine the dissolution time of amorphous Letermovir.

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Additional studies have shown that the concentration of amorphous Letermovir in solution can be increased from 16% (120 mg/dose Letermovir in 750 mg/dose water) to 24% (120 mg/dose Letermovir in 500 mg/dose water). In addition, you can increase the amounts of L-arginine and hypromellose/hydroxypropylcellulose contained in the drug. There was no significant difference in the solubility of Letermovir in solutions containing hypromellose and hydroxypropylcellulose. Both solutions were used in subsequent granulation experiments.

Carrying out granulation was accompanied by difficulties. Since the amount of granulating liquid was relatively large to ensure dissolution of all Letermovir, granulation was carried out in a step to prevent excessive wetting of the support. Due to the repeated granulation and drying procedures, the hardness of the resulting granules after drying was very high, which prevented the grinding of the granules. Manual pressing of the resulting tablets produced tablets with the required hardness. However, the tablets did not disintegrate after 30 minutes and the dissolution of the tablets at a pH value of 1.0 and with the addition of 0.2% SDS was too slow.

To reduce the amount of granulation solution required in the granulation medium, ethanol and acetone were used as co-solvents. However, compared to the use of water, the use of acetone did not provide significant processing advantages. Attempts to eliminate a large number of drying and granulation stages by increasing the amount of colloidal anhydrous silicon dioxide contained in the preparation also failed.

To eliminate the large number of granulation and drying steps required for high shear granulation of Letermovir, fluidized bed granulation was used. Granulation occurred without much difficulty and could be well controlled. The resulting preparations from the experimental batches contained different amounts of disintegrants, but all three batches had disintegration times (in water) ranging from 12 to 15 minutes. These disintegration times were less than the disintegration times of the high shear granulation pilot batches, and dissolution was slower than the high shear granulation pilot batch formulations.

1c) General conclusion about drugs containing amorphous Letermovir with the addition of L-arginine

The development of drugs containing Letermovir with the addition of L-Arginine carried out in the laboratory did not lead to the production of a method and product with the necessary characteristics. The dissolution of the resulting pilot batch formulations was also too slow for an immediate release finished drug. Subsequent attempts to improve dissolution by processing using high shear granulation and fluidized bed granulation were not successful. It turned out that L-arginine does not have a positive effect on the dissolution characteristics of Letermovir. Therefore, the inclusion of L-arginine in solid formulations cannot be expected to have a beneficial effect on the bioavailability of Letermovir.

2) Solubility of Letermovir

The present inventors conducted a solubility study of amorphous Letermovir to investigate its biopharmaceutical status using standardized parameters. The inventors of the present invention have followed the guidelines of the established Biopharmaceutical Classification System (BCS).

Using the BCS system can roughly predict the rate-limiting stage of intestinal absorption following oral administration (see Arik Dahan et al., Prediction of Solubility and Permeability Class Membership: Provisional BCS Classification of the World's Top Oral Drugs. The AAPS Journal, Vol. 11 , No. 4, December 2009 DOI: 10.1208/s12248-009-9144-x).

According to the BCS, the solubility class limit is based on the maximum dose of the finished IR product. Using the approach described in BCS, the equilibrium solubility of amorphous Letermovir at physiological pH values was determined. The dependence of the solubility of amorphous Letermovir on pH value was studied at 37±1°C in an aqueous medium with a pH value in the range of 1-7.5. A sufficient number of pH values were studied to accurately determine the dependence of the solubility of amorphous Letermovir on pH value. The number of pH values used to determine solubility was based on the ionization characteristics of Letermovir. At least three replicate experiments were carried out to determine solubility at each pH value.

In more detail, the methodology was as follows:

The maximum dose of Letermovir was approximately 240 mg. When dissolved in 250 ml, it corresponds to a concentration of 0.96 mg/ml. The solubility of Letermovir was determined after stirring at 37±1°C for 24 hours in standard buffer solutions in accordance with the manual

FDA - Guidance for Industry, Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System.

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Table 3. Solubility of Letermovir in the pH range from 1 to 7.5

pH Letermovir solubility (mg/ml) 1 > 0.9 2.9 (pKai-1) 0.8 3.9 (pKaD 0.4 4.9 (pKai+1) 0.4 7.5 >ι,ο

The results of the study of the solubility of Letermovir are given in table. 3 and they confirm that Letermovir cannot be considered as a highly soluble drug substance. As shown in table. 3, the solubility of Letermovir in the pH range of 1 to 7.5 varies from 0.4 to > 1 mg/ml. These results indicate the difficulties that will arise when incorporating amorphous API-Letermovir into an orally administered IR tablet formulation.

3) Isolation of amorphous Letermovir

To carry out subsequent tabletting of orally administered drugs containing amorphous Letermovir, the API must first be isolated from the organic solution in solid amorphous form. In addition, the API must be dried without degrading its physical and chemical characteristics and must have residual solvent content that meets the requirements of the current ICH guidelines.

a) Isolation by drying in a roller dryer

A vacuum roller dryer (GMF Gouda, Type VT2/4.75) was used to obtain amorphous Letermovir of pharmaceutical grade. The roller dryer had the following characteristics:

Drum diameter: 0.2 m

Drum length: 0.475 m

Heated surface: 0.6 m

Temperature: 40-65°C, preferably 60°C

Pressure: 200 mbar

In more detail, the methodology was as follows:

Acetone containing 30% Letermovir was injected at a rate of approximately 1.2 kg/h through an adjustable slit (best results were obtained with a slit width of 0.15 mm). From 9.8 kg of initial solution in acetone, 2.35 kg of solid amorphous Letermovir can be obtained. The content of residual acetone ranged from 1.7 to 3%; however, by carrying out a subsequent drying step, for example in a vacuum dryer or cone dryer, the amount of remaining acetone can be reduced to <0.5%.

The specific surface area of this product was <1 m ² /g and a tablet of acceptable quality was obtained only by wet granulation.

The amorphous Letermovir contained in the following typical preparation according to the present invention, isolated by roller drying and further processed by wet granulation, had a degree of dissolution suitable for the purposes of the present invention, i.e. component >50% no later than 30 minutes.

Table 4. Typical preparation containing amorphous Letermovir dried in a roller dryer

Material - granulate (wet) mg/dose Letermovir (roller dried) 30.00 Microcrystalline cellulose 28.00 Colloidal anhydrous silica 0.500 Povidone 25 2,500 Purified water 25.00 Granulate, amount 61.00 Material - final mixture mg/dose Wet granulate 61.00 Microcrystalline cellulose 8.50 Colloidal anhydrous silica 1.00 Magnesium stearate 0.75 Final mixture, amount 75.00

3b) Isolation by sedimentation

A mixture of the system (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid -methyl ester {(4S)-8fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]- 3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid (1:1 salt) (30.8 kg), sodium bicarbonate (16.4 kg) and water (315 L) was stirred in MTBE (160 L). The resulting phases were separated and the organic phase was treated with 35 L of 7% sodium bicarbonate solution. The resulting phases were re-separated and the organic phase was treated with 125 L of 4% sodium hydroxide solution. The mixture was refluxed. The solvent was distilled to dryness. The remaining contents of the reactor were stirred at 55-60°C

- 24 043692 for another 5 hours. MTBE (160 L) and water (65 L) were added to the mixture at 22°C with stirring. The resulting phases were re-separated and the organic phase was extracted with 6% aqueous sodium chloride solution (30 L). The aqueous phases were recombined and mixed with water (25 L) and MTBE (160 L). The pH was adjusted to 6.5 with 1 N. hydrochloric acid solution. The organic phase was separated, the solvent was carefully distilled to dryness and the residue was dissolved in acetone (approximately 75 l). The solvent was replaced with acetone by carrying out 6 stages of distillation, in each case the volume of the solvent was 130 l. The product was then precipitated by adding the remaining solvent (about 60 L) with excess water (492 L) while stirring (61 rpm) at room temperature. After centrifugation, the isolated product was dried at 40-80°C in a vacuum drying oven equipped with a screw roller for crushing. This procedure prepared 16.5 kg of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-(2-methoxy-5-trifluoromethylphenyl)-3,4dihydroquinazoline -4-yl}acetic acid in the form of an amorphous compound, the yield was 96.4% of theoretical.

1H NMR (nuclear magnetic resonance) (300 MHz, d ₆ -DMSO): δ = 7.53 (d, 2J=8.4, 1H), 7.41 (brs, 1H), 7.22 (d, 2J =8.5, 1H), 7.09-7.01 (m, 2H), 6.86 (m, 2H), 6.45 (dd, 2J=8.2, ³ J=1.8, 1H ), 6.39-6.34 (m, 2H), 4.87 (t, ² J=7.3, 1H), 3.79 (brs, 3H), 3.68 (s, 3H), 3 .50-3.38 (m, 4H), 2.96-2.75 (m, 5H), 2.45-2.40 (m, 1H) ppm; MS (mass spectrometry) (IAP-ER (atmospheric pressure ionization - electrospray), negative): m/z = 571 [(M-H), 100%];

The choice of suitable conditions for distillation, carried out before the separation itself, can extremely reduce the possible content of residual MTBE and mesityl oxide. To prevent spontaneous condensation of acetone in mesityl oxide during solvent exchange during the distillation steps, it is necessary to maintain the temperature as low as possible by using a vacuum (200 mbar).

In particular, complete drying of acetone-containing Letermovir in vacuum gives an acetone content of <0.5%, which corresponds to pharmaceutical grade (according to ICH guidelines), and a water content of <2%. API-Letermovir remains in an amorphous state and has a specific surface area of 1.2-2 m ² /g.

These characteristics make it possible to directly use it for the preparation of the drug in tablet form by dry granulation carried out using a roller compaction.

3c) Effect of organic solvents on the precipitation of Letermovir

The effect of organic solvents on the precipitation of Letermovir was studied.

All results described in the present invention are based on appropriate laboratory studies.

The solvent exchange and precipitation procedure was simulated using the readily available amorphous API-Letermovir and five different test solvents.

The specific organic solvents used in this study were selected based on the following conditions:

To get a more complete picture, a specific selection of solvents differing in structure was used. Solvents must be miscible with water to be used in the precipitation method. Only solvents suitable for use in the method were tested, i.e. those that have acceptable toxicity, high volatility and low cost. Therefore, solvents having a high boiling point such as DMF, DMSO, NMP, etc., or solvents having a high toxicity such as glyme (1,2-dimethoxyethane) were not used in this study.

The corresponding solvents tested were methanol, ethanol, tetrahydrofuran (THF), methyl ethyl ketone (MEK; 2-butanone) and acetonitrile (ACN).

A sample of Letermovir (5 g dose) was dissolved in MTBE (26.5 ml). Each solvent was distilled off at 60°C and a pressure of 1 atm. Solvent (13.5 ml) was added and distilled under reduced pressure (200 mbar) at a temperature of not more than 40° C., then solvent (21.5 ml) was added again and distillation was repeated. This stage was carried out 5 times, then another 10 ml of solvent was added. While stirring at ambient temperature, this solution was added to water (160 ml, purified by reverse osmosis) over 30 min, and the product precipitated. The suspension was stirred for another 1 hour, the solid was isolated by filtration, washed twice with water (each time 5 ml, purified by reverse osmosis) and dried in a vacuum oven at 45°C for 24 hours.

After this, the first intermediate sample was taken and drying was continued for another 63 hours to investigate the effect of prolonged drying. Then a second sample of material was taken.

HPLC purity and residual solvent content (RCS) were determined using reverse phase gradient HPLC for purity determination.

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Device: HPLC system with UV detection Column: Prodigy ODS III, 3 µm; 150x3.0mm Mobile phase A: 0.7 ml of 85% phosphoric acid solution is added to 1.36 g of potassium dihydrogen phosphate and dissolved in water, which is added to a volume equal to 1000.0 ml Mobile phase B: acetonitrile Flow rate: 0.5 ml/min Gradient mode: 0 min 20% B 40 min 45% B 50 min 80% B 65 min 80% B 70 min 20% B 75 min 20% B Detection: UV detection at 210 nm, 4 nm bandwidth Temperature: 55°C Injected volume: 3 µl Auto sampler temperature: 5°С Duration of analysis: 75 min

and static gas chromatography using the method of analyzing the headspace above the product

Device Column gas chromatograph, e.g. Agilent 6890 DB-WAXetr, length 30 m, internal diameter 0.32 mm, film thickness 1 µm Carrier gas, flow rate nitrogen, 0.9 ml/min (constant flow rate) headspace sample vessel pressure 120 kPa Injector Temperature Split Flow Velocity Detector/Temperature Combustible Gases: Hydrogen 150°C 4.5 ml/min FID/250°C 40 ml/min Air 450 ml/min Make-up gas (N ₂ ) Furnace temperature program: 25 ml/min Initial temperature Holding time Heating rate Final temperature Holding time Cooling rate Final temperature 40°C 8 min 20 K/min 70°C 3 min 20 K/min 50°С

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Holding time 3 min

Heating speed 15 K/min

Final temperature 220°C

Holding time 3 min

Analysis duration 30.8 min

Equipment automatic device for taking samples from the headspace, e.g. G1888 Sample temperature Pin temperature Transfer temperature GC cycle time Equilibration time Equilibration time 100°С 220°C 230°C 40 min 30 min 1 min

before the first

experiment Number of extractions 1 Shaking during 1 (slow) establishing balance Valve operating times sealing time: 0.25 min loop filling time: 0.20 min time to establish equilibrium in the loop: 0.05 min injection time: 0.50 min Injected volume Results of study 3c) 1 ml

When carrying out this isolation method, the use of all solvents, with the exception of MEK (see below), provided basically similar precipitation, filtration, and washing.

In all cases, there was no noticeable change in the chiral purity of the starting material. Therefore, this study aims to determine the purity and residual solvent content. The results of physical studies are summarized in the table below. 5.

Table 5. Results of physical studies of precipitated Letermovir, given in terms of HPLC purity and residual solvent content (RCS)

No. Solvent Release of Letermovir HPLC purity 1 ^υ RCS 1 ²⁾ HPLC purity 2 ^υ RCS 2 ²⁾ Notes 1 (Acetone) ... 3) 99.76% (123) - - Starting material 2 MeOH 90% 99.87% 10 99.87% 10 3 EtOH 91% 99.38% 0.52% 7 99.70% 0.23% 3 4 THF 87% 99.54% 0.35% >30,000 99.55% 0.36% >20,000 5 MEK 78% 99.82% >20,000 99.80% >10,000 Sticky residue 6 ACN 91% 99.91% 34 99.93% 4 7 Acetone 92% 99.88 3516 99.87 1247 Comparative experiment

1) the value given in the cell indicates the purity of Letermovir according to HPLC data; The percentage of impurities equal to or greater than 0.10% is given below the value for Letermovir.

²⁾ Residual solvent content (RCS) is given in ppm. According to ICH guidelines, the limit values expressed in ppm are as follows: methanol: 3000; ethanol: 5000; THF: 720; MEK: 5000; ACN: 410; Acetone: 5000.

³⁾ The yield of this batch is not taken into account, since the method uses methyl {(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy- 5-(trifluoromethyl)phenyl]-3,4dihydroquinazolin-4-yl}acetate (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (1:1) (SCDT).

When described in more detail, the results were as follows:

3d) Methanol as an organic solvent

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In principle, methanol can be used to carry out the precipitation step, but from independent experiments it has become apparent that when harsh conditions (elevated temperature) are used, transesterification by reaction with lower alcohols such as methanol or ethanol can occur.

3e) Ethanol as an organic solvent

The use of ethanol led to the formation of a by-product, and surprisingly it was found that its amount decreases upon drying, but is not completely removed. Since the nature of this by-product is unknown, the reason for this supposed reversibility is not discussed in the present invention.

As with methanol, the ethanol content of the final product was negligible, being only 7 and 3 ppm after long drying, respectively.

3f) THF as organic solvent

The use of THF also resulted in the formation of an unknown impurity of approximately 0.35%, which remained constant after drying.

In addition, residual THF was shown to be very difficult to remove, with amounts exceeding the limit of 720 ppm by at least 30 times, and residual amounts of more than 20,000 ppm

g) MEK as organic solvent

While the use of MEK provided very acceptable HPLC purity, it was found to be unsuitable for use in the process: the precipitate was sticky, which would likely make filtration difficult on an industrial scale. The results of the residual solvent analysis showed that MEK is essentially as unsuitable as THF: the amount of residual solvent of well over 10,000 ppm (after long drying) exceeds the limit value of 5,000 ppm at least at least 2 times. This solvent should be considered unsuitable.

3h) Acetonitrile as an organic solvent

The use of acetonitrile did not cause any difficulties. Although its toxicity and therefore the strict limit (410 ppm) could raise concerns regarding residual solvent, the determined contents were much less than 410 ppm after just 1 day of drying. and they decreased to below the detection limit of 5 ppm after drying for another 63 hours (amount: 4 ppm).

All of these results favored acetonitrile, but from independent experiments it became apparent that some degree of racemization could occur in this solvent under the influence of bases and at elevated temperatures.

3i) Acetone as an organic solvent

Surprisingly, it turned out that the use of water-soluble acetone provides the best results for the isolation of Letermovir. Acetone does not affect the quality of Letermovir at all and can be removed by drying so that the residual content is much less than the limit of 0.5% according to the ICH guidelines, thereby obtaining a product that can be directly used for inclusion in preparations for oral and intravenous administration (to obtain API-Letermovir, intended for inclusion in preparations for intravenous administration, water for injection was used at the precipitation stage).

In the context of the above results, the use of acetone provides several advantages:

it is highly volatile, so it is quite easy to remove;

it has low toxicity, so there are acceptable levels of residual solvent;

it is not reactive with API-Letermovir and therefore there are virtually no by-products.

3j) Summary and Conclusion

When conducting research in laboratory conditions, it was found that of the solvents studied, ethanol, THF and MEK are not suitable due to insufficient quality of the product or difficulties during the method. Although the use of methanol and acetonitrile provided good product purity by HPLC, their use is not recommended and possible side reactions include transesterification and racemization, respectively.

Although acetonitrile may be a good substitute, from a toxicological and economic point of view acetone is preferred for use as an organic solvent for the precipitation of the Letermovir API of the present invention.

4) Galenic preparations/tableting techniques

The present inventors have developed the following herbal formulations and processing methods suitable for incorporating amorphous Letermovir into immediate release formulations.

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The excipients used and their purposes are described in Table. 6.

Table 6. Excipient/purpose when used in herbal preparations

Inert filler Purpose microcrystalline cellulose filler/binder colloidal anhydrous silica glidant agent povidone 25 polymer/binder croscarmellose sodium salt baking powder Magnesium stearate lubricant ethanol processing aid acetone processing aid purified water processing aid

To study the dissolution of the immediate release drug, a test was carried out using the Ph.Eur method. 2.9.3 Apparatus 2 at a blade rotation speed of 50 rpm.

The proposed dissolution procedure is described below. Reverse phase HPLC technique was used to analyze the samples.

Operating conditions of the apparatus for dissolution research:

Equipment: Sample size: Temperature: Rotational speed: Wednesday: Ph.Eur. 2.9.3 Apparatus 2 (bladed) 6 tablets 37.0±0.5°С 50 rpm 0.1 n. HC1 solution/0.2% sodium lauryl sulfate solution

Medium volume: 1000 ml Sample volume: 1 ml Sampling time: 15, 30 and 45 min HPLC conditions: Column: Waters Symmetry Nucleosil 100 C18, 40 mmx4.0 mm, 10 µm

Detection wavelength: 256 nm

Approximate 4 min experiment duration:

The approximate time 1.3 min holding: Column temperature: 40°C Injected volume 20 µl Flow rate: 1.5 ml/min Mobile phase: pH 4.0 buffer/acetonitrile; 55/45 rev/rev

Research and related substances

Reverse phase HPLC in gradient mode was used to identify the finished drug, analyze and determine the degradation products.

Experiment conditions:

Column: Intertsil ODS III, 5 µm, or equivalent Solvent: acetonitrile/0.1 N. HC1 solution; 3+7 (rev/rev) Eluent: A: water, pH 2.40; B: acetonitrile Detection wavelength: 235 nm Column temperature: Injected volume: 40°C 15 µl Flow rate: Duration of the experiment: 1.0 ml/min 30 min

4a) Preparations obtained by wet granulation containing roller-dried and precipitated amorphous Letermovir

High shear wet granulation using purified water as a processing aid resulted in a good granulate in which the material was fully cohesive, soft and voluminous. Using purified water as a processing aid, it was possible to perform high shear wet granulation using both roller dried and precipitated API. Quantitative composition

- 29 043692 of the drug obtained by wet granulation with high shear force, containing Letermovir dried in a roller dryer and precipitated, is given in table. 7.

Table 7. Composition of the preparation obtained by wet granulation with high shear force, containing letermovir dried in a roller dryer and precipitated

Material - granulate (wet) mg/dose Letermovir (roller dried or precipitated) 30.00 Microcrystalline cellulose 28.00 Colloidal anhydrous silica 0.50 Povidone 25 2.50 Purified water 25.00 Granulate, amount 61.00 Material - final mixture mg/dose Wet granulate 61.00 Microcrystalline cellulose 10.00 Croscarmellose sodium salt 2.25 Colloidal anhydrous silica 1.00 Magnesium stearate 0.75 Final mixture, amount 75.00

Granules containing precipitated Letermovir (40311P18) appeared stronger than granules containing roller-dried Letermovir (40311P17). Granules containing Letermovir dried in a roller dryer had better flowability than granules containing precipitated Letermovir. As a result of this apparent difference in the flowability of the powders, significant differences in the compressive forces measured during the preparation of tablets from granules containing precipitated Letermovir were observed. Due to such differences in compressive forces, tablets made from granules containing Letermovir dried in a roller dryer had a more uniform mass and thickness (shown in Tables 8 and 9).

Table 8. Comparison of IPC results for preparations containing roller-dried (40311P17) and precipitated (40311P18) Letermovir

physical characteristics Nominal value Actual value 40311Р17 40311Р18 Average weight [mg] 75+3% (73-77) 75 81 Lowest weight [mg] 68 71 69 Maximum weight [mg] 82 78 91 Diameter [mm] 5.4-5.6 5.5 5.5 Thickness [mm] define 3.0-3.1 2.9-3.3 Hardness [N] define 100 117 Fragility [%] < 1.0 0.2 0.2 Decay in SCHO [min] < 30 10 min and 30 s - 13 min and 15 s 20 min and 00 s - 23 min and 30 sec

Tablets containing Letermovir (40311P17) dried in a roller dryer are characterized by faster dissolution (the results are shown in Table 9).

Table 9. Comparison of the results of dissolution of drugs containing Letermovir dried in a roller dryer (40311P17) and precipitated (40311P18)

Time [min] 40311Р17 40311Р18 Dissolution rate [%] With * ^relative G%1 Dissolution rate [%] With * ^relative G%1 15 64 19.8 24 19.1 thirty 95 2.1 82** 9.1 45 96 2.5 104 6.8 60 97 2.0 107 7.1

* _Sothocut . - relative standard deviation ** Note: individual values - 68%, 87%, 88%, 79%, 82%.

Conclusion to 4a)

When using a mixture of purified water/povidone solution as a technological additive, it was possible to granulate both types of isolated Letermovir. Tablets made from granules incorporating roll-dried Letermovir had a more uniform thickness and weight than tablets made from granules incorporating precipitated Letermovir when the granules were produced by high shear wet granulation. In addition, tablets containing roller-dried Letermovir are characterized by faster dissolution within up to 30 minutes than tablets containing precipitated Letermovir.

4b) Letermovir dried in a roller dryer

The present inventors also tested only roller-dried Letermovir. To improve tablet disintegration and reduce changes in solubility, the amount of disintegrant, croscarmellose sodium salt, was increased from 3 to 5%. The amount of microcrystalline cellulose was reduced accordingly to maintain tablet weight. The quantitative composition of the drug is given in table. 10.

Table 10. Typical preparation containing roller-dried Letermovir, which has a high content of croscarmellose sodium salt

Material - granulate (wet) mg/dose Letermovir (roller dried) 30.00 Microcrystalline cellulose 28.00 Colloidal anhydrous silica 0.50 Povidone 25 2.50 Purified water 25.00 Granulate, amount 61.00 Material - final mixture mg/dose Wet granulate 61.00 Microcrystalline cellulose 8.50 Croscarmellose sodium salt 3.75 Colloidal anhydrous silica 1.00 Magnesium stearate 0.75 Final mixture, amount 75.00

Results for 4b)

Granulation and tableting were carried out without difficulty and the IPC (process control) results are shown in table. 11 and 12.

Table 11. IPC results for a preparation obtained by wet granulation containing roller-dried Letermovir, which has an increased content of croscarmellose sodium salt

physical characteristics Nominal value Actual value Average weight [mg] 75+3% (73-77) 74 Lowest weight [mg] 68 71 Maximum weight [mg] 82 81 Diameter [mm] 5.4-5.6 5.5 Thickness [mm] define 3.0-3.1 Hardness [N] define 87 Fragility [%] < 1.0 θ,ι Decay into H ₂ O [min] < 30 14 min and 00 s - 16 min and 20 s

Table 12. Results of a study of the dissolution of a preparation obtained by wet granulation containing Letermovir dried in a roller dryer, which has a high content of croscarmellose sodium salt

Time [min] Dissolution rate [%] ^relative [%] 15 72 10.7 thirty 99 1.3 45 99 1.3 60 100 1.4

Conclusion

All IPC and dissolution test results were in accordance with the requirements given in Table. 21. A standard deviation of approximately 1.3% at 30, 45 and 60 minutes was pharmaceutically acceptable.

5) Dry granulation of roller-dried and precipitated amorphous Letermovir

Simultaneously with the wet granulation experiments, dry granulation experiments were also carried out using a Kilian rotary press to compress the isolated Letermovir to obtain pressed blanks, followed by grinding of the compressed blanks using a conical mill using the composition given in table. 13.

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Table 13. Typical product containing Letermovir obtained by dry granulation

Material - granulate (dry)__mg/dose____________

Letermovir (dried in a roller dryer) 30.00

Microcrystalline cellulose 18.00 Colloidal anhydrous silica 0.50 Povidone 25 2.50 Magnesium stearate 0.30 Granulate, amount 51.30 Material - final mixture mg/dose Dry granulate 51.30 Microcrystalline cellulose 20.00 Croscarmellose sodium salt 2.25 Colloidal anhydrous silica 1.00 Magnesium stearate 0.45 Final mixture, amount 75.00

Results for 5)

It was possible to carry out dry granulation, grind the dry granulates and obtain the final mixture on a small scale. All IPC results were in accordance with the requirements and they are shown in table. 14.

Table 14. IPC results for a typical Letermovir-containing product prepared by dry granulation

physical characteristics Nominal value Actual value Average weight [mg] 75+3% (73-77) 75 Lowest weight [mg] 68 69 Maximum weight [mg] 82 83 Diameter [mm] 5.4-5.6 5.5 Thickness [mm] define 3.0-3.1 Hardness [N] define 92 Fragility [%] < 1.0 0.2 Decay into H ₂ O [min] < 30 9 min and 40 sec - 17 min and 20 sec

However, as shown in table. 15, the degree of dissolution was less than 80% no later than 30 minutes.

Table 15. Results of a dissolution study of a typical preparation containing Letermovir obtained by dry granulation

Time[min] Dissolution rate [%] ^REL. [%] 15 35 43.3 thirty 73 16.1 45 103 3.4 60 106 4.3

Conclusion

It was possible to manufacture this preparation using dry granulation on a small scale. The dissolution was worse than the target specification. In addition, the standard deviation value for the dissolution rate after 15 min was too high, suggesting that the dissolution rate may be limited by the initial disintegration of the tablet. To improve tablet disintegration, the amount of croscarmellose sodium salt was also increased from 3 to 5% and the amount of microcrystalline cellulose was reduced accordingly to maintain tablet weight. Increasing the amount of disintegrant, croscarmellose sodium, also ensured faster dissolution of the kernels, as shown above in the case of wet granulation. The results were in accordance with the requirements. Dissolution was further improved if disintegrants were included in the dry granulate.

6) Dry Granulation - Comparison of Roll Dried API and Sedimented API

Experiments were carried out in order to find out whether it is possible to use dry granulation for both types of Letermovir, dried in a roller dryer and deposited. The quantitative composition of the drug is given in table. 16.

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Table 16. Preparation obtained by dry granulation containing letermovir dried in a roller dryer and precipitated

Material - granulate (dry) mg/dose Letermovir (roller dried; precipitated) 30.00 Microcrystalline cellulose 16.50 Colloidal anhydrous silica 0.50 Povidone 25 2.50 Croscarmellose sodium salt 1.50 Magnesium stearate 0.30 Granulate, amount 51.30 Material - final mixture mg/dose Dry granulate 51.30 Microcrystalline cellulose 20.00 Croscarmellose sodium salt 2.25 Colloidal anhydrous silica 1.00 Magnesium stearate 0.45 Final mixture, amount 75.00

Dry granulation, grinding of dry granulates and preparation of final mixtures were carried out without difficulty using roller-dried (40311P15) and precipitated (40311P16) Letermovir. Granules containing precipitated Letermovir had better flowability than granules containing roller-dried Letermovir. As a result of this difference in the flowability of the powders, significant differences in the compressive forces measured during the preparation of tablets from granules containing roller-dried Letermovir were observed. As a result, tablets made from granules containing precipitated Letermovir had a more uniform mass and thickness. For similarities, see table. 17, which shows the corresponding IPC results.

Table 17. IPC results for a dry granulated formulation containing roller-dried (40311P15) and precipitated (40311P16) Letermovir

physical characteristics Nominal value Actual value 40311Р15 40311Р16 Average weight [mg] 75+3% (73-77) 80 74 Lowest weight [mg] 68 75 69 Maximum weight [mg] 82 87 78 Diameter [mm] 5.4-5.6 5.5 5.5 Thickness [mm] define 3.0-3.3 2.9-3.0 Hardness [N] define 93 92 Fragility [%] < 1.0 0.1 0.2 Decay into H ₂ O [min] < 30 9 min and 00 s - 13 min and 00 s 10 min and 00 s - 13 min and 20 s

The corresponding results of the dissolution study are given in table. 18.

Table 18. Dissolution test results; a preparation obtained by dry granulation containing letermovir dried in a roller dryer (40311P15) and precipitated (40311P16)

Time [min] 40311Р15 40311Р16 Dissolution rate [%>] WITH * ^relative G%1 Dissolution rate [%] Q* ^REL. G%1 15 60 8.2 50 14.3 thirty 100 1.8 89 2.2 45 102 1.3 91 2.6 60 102 1.3 93 2.0

General conclusion

Initial testing during the development phase began by investigating wet granulation and dry granulation processing. Initial attempts at high shear wet granulation using organic solvents were unsuccessful. However, when using water as a processing aid, the granulation process improved.

Dry granulation processing is preferred over wet granulation processing because the dry granulation technique has no batch size restrictions and is expected to be easier to scale up in a reproducible manner. The rate of dissolution can be increased by accelerating the disintegration of the tablet by increasing the amount of disintegrant contained in the preparation. The best results are obtained with the addition of intragranular disintegrants.

Studies were conducted using two types of amorphous Letermovir, which were obtained in two different ways, namely roller-dried Letermovir and precipitated Letermovir.

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Several studies have found that roller dried API is more suitable for wet granulation processing and precipitated API is more suitable for dry granulation processing. Using both techniques, 30 mg tablets were produced with acceptable physical characteristics to meet the requirements and a sufficient degree of dissolution.

In addition, one study using the dry granulation technique using the highest dose in the homologous series was successfully conducted. Physical characteristics and degree of dissolution were acceptable for all dose levels.

7) Typical preparations containing precipitated API at four doses proposed in the present invention

Table 19. Typical preparations containing Letermovir at doses equal to 30, 60, 120 and 240 mg

Substance Dose equal to 30 mg |mg/dose] Dose equal to 60 mg [mg/dose] Dose equal to 120 mg [mg/dose] Dose equal to 240 mg [mg/dose] Dry granulate — -- -- — Letermovir 30,000 60,000 120,000 240,000 Microcrystalline cellulose 16,500 33,000 66,000 132,000 Colloidal anhydrous silica 0.500 1,000 2,000 4,000 Povidone 25 2,500 5,000 10,000 20,000 Croscarmellose sodium salt 1,500 3,000 6,000 12,000 Magnesium stearate 0.300 0.600 1,200 2,400 Amount, granulate 51,300 102,600 205,200 410,400 Final mixture/tablet — -- -- — Granulate 51,300 102,600 205,200 410,400 Microcrystalline cellulose 20,000 40,000 80,000 100,000 Croscarmellose sodium salt 2,250 4,500 9,000 18,000 Colloidal anhydrous silica 1,000 2,000 4,000 8,000 Magnesium stearate 0.450 0.900 1,800 3,600 Amount, final mixture/tablet 75,000 150,000 300,000 600,000 Film-coated tablet - - - - Macrogol 600 0.460 0.900 1,800 3,600 Hypromellose 1,380 2,700 5,400 10,800 Purified water* 14,310 28,000 56,000 112,000 Titanium dioxide 0.370 0.720 1,440 2,880 Yellow iron oxide 0.090 0.180 0.360 0.720 Purified water* 6,389 12,500 25,000 50,000 Film-coated tablet 77,300 154,500 309,000 618,000

8) Roller compaction for dry granulation of precipitated Letermovir

Dry granulation was then carried out using a roller press. Roller compaction is a more scalable dry granulation technique than the compacted and milling process used to produce the original batches. When using the Gerteis Minipactor® roller press, the flowability of the powder was also improved compared to the flowability obtained when dry granulation was carried out using a tableting machine (aggregation). The composition of the drug was further optimized by using microcrystalline cellulose, which has larger particles. The original and optimized preparations are given in the table below. 20.

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Table 20. Optimized preparations of precipitated Letermovir as dry granulates for roller compaction

Component Original drug Optimized drug mg/dose Core — — 75.00 Dry granulate — — 51.30 Magnesium stearate MF-2 V, from plant source MF-2 V, from plant source 0.30 Magnesium stearate MF-2 V, from plant source MF-2 V, from plant source 0.45 Povidone Polyvinylpyrrolidone Polyvinylpyrrolidone 2.50 Croscarmellose sodium salt Ac-Di Sol Ac-Di Sol 1.50 Croscarmellose sodium salt Ac-Di Sol Ac-Di Sol 2.25 Microcrystalline cellulose Emcocel 50M Emcocel 50M 16.50 Microcrystalline cellulose Emcocel 50M Avicel PH200 20.00 Letermovir besieged besieged 30.00 Colloidal anhydrous silica Pyrogenic silica Cab-o-Sil, grade M5P Pyrogenic silica Cab-o-Sil, grade M5P 0.50 Colloidal anhydrous silica Pyrogenic silica Cab-o-Sil, grade M5P Pyrogenic silica Cab-o-Sil, grade M5P 1.00

Results for 8)

The dry granulation technique was then scaled up to increase the batch size to 12 kg without negatively impacting compaction characteristics. A homogeneity study of samples collected at the beginning, middle and end of the tableting procedure for tablets containing doses equal to 60 mg and for a representative tablet sample containing a dose equal to 240 mg showed uniformity of distribution of Letermovir within the tablet mixture. The results of the solubility study for tablets containing all doses were acceptable.

9) Proposed requirements for the shelf life of amorphous Letermovir included in the drug in tablet form

Table 21. Proposed requirements and methods for studying tablets containing Letermovir

Study Requirement Research methodology Appearance Yellow/brownish Visual Study Requirement Research methodology yellow round tablets without markings Identification The retention time (HPLC) for Letermovir should match that of the reference sample RP-HPLC method** Identification The spectrum should be comparable to the spectrum of the reference material IR-FS*** Activity Research 90.0-110.0% RP-HPLC technique Special unknown impurities No more than 0.2% No more than 0.2% Known impurities Total impurity content No more than 3.0% Dissolution degree Q = 80% in 30 min Method Ph.Eur. 2.9.3 USP <711> Uniformity of single dosage form Meets requirements Ph.Eur 2.9.40> Water content Specify values Ph.Eur 2.5.12 Microorganism counting Total number of aerobic microorganisms: Total total amount of yeasts and molds: No Escherichia coli No more than 1000 CFU/g No more than 100 CFU/g No more than 100 CFU/g USP <61> USP <62> Ph.Eur. 2.6.12, 2.6.13

* CFU - colony forming unit ** RP - reverse phase *** IR-FS - Fourier transform infrared spectroscopy

10) Long-term stability

To confirm the stability of tablets containing precipitated amorphous Letermovir, long-term stability studies were carried out by examining color, dissolution, degradation products and analysis at regular intervals.

- 35 043692

The analysis methods used for these studies are given in Table. 21. In addition, decomposition studies, water content and hardness/breaking force determinations were carried out as informative studies.

For the study of each dose value, samples of one batch of tablets containing precipitated Letermovir, packaged in 45 ml HDPE (high density polyethylene) bottles equipped with child-resistant caps, were stored at 25°C/60% relative humidity. and at 40°C/75% relative humidity. The results of a stability study after storage for 36 months were presented.

Additional studies of forced decomposition were carried out. To study each dose of Letermovir, one batch of tablets was stored at 60°C for 3 months. To study hydrolysis resistance, one batch of tablets containing a dose of 20 mg was stored outdoors at 40°C/75% relative humidity for 3 months.

Conclusion for Stability Study

Over the entire study period (36 months), all characteristics studied (i.e., appearance, dissolution, amount of degradation products, and analytical results) met shelf life requirements. Letermovir is stable under long-term storage conditions (at 25°C/60% relative humidity) and under accelerated storage conditions (at 40°C/75% relative humidity); no significant changes were observed. Only a slight increase (no more than 0.2%) in the amount of decomposition products was detected. The largest amount of a single decomposition product was less than 0.5%. Typical stability study results are shown in the tables presented in FIGS. 8a-c.

Since the results obtained from the 36 month stability study (real time data at 25°C/60% RH) were fully consistent with the shelf life requirements, and given that There was no significant increase in the amount of degradation products, no evidence of crystallization during the storage period, or no other adverse changes in quality, and a shelf life of 36 months was established for the preparations containing both doses tested.

11) Absolute bioavailability of Letermovir in an amorphous state

Objectives of the pharmacokinetic study conducted in the clinical trial for cohort 1:

Comparison of the absolute bioavailability of Letermovir after oral administration of 30 mg of Letermovir in an amorphous state and with intravenous administration of 30 mg of Letermovir over 30 minutes as a solution in 150 ml of 0.9% saline.

Scheme

The study for Cohort 1 was an open-label, randomized (with regard to the order of administration), single-center crossover (2 periods) and included 12 healthy women. In one period, subjects were administered a single dose of Letermovir 30 mg intravenously over 30 minutes (reference) and in the other period subjects were administered a single dose of amorphous Letermovir 30 mg orally (study). In both periods, subjects were hospitalized from Day 1 to Day 4 (within 72 hours of the Day 1 dose). The washout period between periods (i.e., dosing) was at least 1 week. Cohort 1 assessed the results of a dose of 30 mg (see Figs. 7a and 7b).

Techniques

Letermovir plasma concentrations were determined at a lower limit of quantitation (LOQ) of 1.00 ng/mL. Pharmacokinetic parameters AUC _0. „ (AUC - area under the concentration-time curve), C _max (maximum plasma concentration), F (absolute bioavailability), AUC0-last, t _max (time to reach C _max ), λz (constant terminal elimination rate), t _1/2z (half-life), CL/F, CL (total plasma clearance after oral administration), Vd/F, Vd (volume of distribution), MVP (mean residence time), AUC ₀ .„/ D (D-administered dose), C _max /D, AUC ₀ . _nseq./D , for cohort 1, was calculated using WinNonlin software using the actual sampling time. Descriptive statistics were used to analyze the results for plasma concentrations and derived pharmacokinetic parameters. Statistics included sample size (n), mean, standard deviation (SD), percentage coefficient of variation (KB, %), geometric mean, mean, minimum value, and maximum value. A statistical study of the absolute bioavailability of Letermovir in cohort 1 was carried out by comparing logarithmic AUC ₀ values. _last and AUC _0. „ obtained with oral administration of Letermovir in the amorphous state (study) and intravenous administration of Letermovir (reference) using a mixed linear effect model. Only paired observations were included in the statistical analysis.

Results of pharmacokinetic studies

See fig. 7a and 7b.

- 36 043692

Conclusions

After administration of one dose of Letermovir, amounting to 30 mg, orally and intravenously (infusion over 30 minutes), the absolute bioavailability of Letermovir according to statistical analysis of the AUC _{was 0-last} . was 76%.

12) Determination of specific surface area using the BET method

Determination of the specific surface area using the BET method was carried out for several batches of precipitated amorphous Letermovir. The same study was carried out for a batch of Letermovir (designated BXR3GBL) obtained in accordance with example 11 in WO 2006/133822. The results of the study are shown in the table below. 22.

Table 22. Determination of specific surface area using the BET method

Lot number or identifying name of Letermovir Specific surface area (SSA), m ² /g; average value obtained using the BET method Precipitated Letermovir (experiment number) 40475297 1.25 40474375 1.46 40483517 1.87 40474463 1.23 40483515 1.03 40483516 1.28 40479189 1.26 40479463 1.45 40479248 1.45 40479434 1.48 40479198 2.09 40483517 1.83 40479198 2.25 40479200 1.30 40479326 1.76 40479201 1.97 40479202 1.69 Amorphous Letermovir prepared according to example 11 in WO2006/133822 Average value obtained using the BET method BXR3GBL batch 0.64

From the results given in table. 22, it can be concluded that the batch of BXR3GBL obtained in accordance with the prior art method described in WO 2006/133822 has an average BET SSA value of 0.64 m ² /g, while the precipitated amorphous Letermovir, proposed in the present invention, has an average BET SSA value ranging from 1.03 m ² /g (experiment number 40483515) to 2.25 m ² /g (experiment number 40479198).

The specific BET technique is characterized by the following conditions:

Principle: nitrogen adsorption at 77 K; Brunauer, Emmett and Teller technique (BET)

Method: volumetric method (method II) in accordance with USP <846>

Device: Tristar 3000/VacPrep 061 (Micromeritics)

Sample weight: approximately 1.5-2.5 g

Sample preparation: degassing in vacuum at 40°C for 2 hours (final vacuum < 2.7 Pa)

Pressure range p/p ₀ : 0.05 - 0.15 (3 experimental values).

13) Determination of particle size distribution using laser diffraction analysis (Mastersizer 2000)

Determination of particle size distribution by laser diffraction analysis was carried out for two batches of precipitated amorphous Letermovir according to the present invention and for a batch of amorphous Letermovir (designated BXR3GBL) obtained in accordance with example 11 in WO 2006/133822 using laser diffraction analyzer Mastersizer 2000 (Malvern Instruments). The results of the study are presented in Fig. 9 (a-c) in the form of three diagrams for the particle size distribution and the numerical values are presented below in table. 23:

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Table 23. Determination of particle size distribution using laser diffraction analysis (Mastersizer 2000) followed by additional determination of specific surface area using the BET method

Lot number or identifying name of Letermovir Average particle size d(0.5), µm Specific area 2 surfaces (SSA), m/g Besieged Letermovir 1300750 9,383 2.1 1300735 8,880 2.18 Letermovir prepared according to example 11 in WO2006/133822 BXR3GBL batch 21,607 1.55

From the results given in table. 23, it can be concluded that the prior art batch of BXR3GBL produced by the method corresponding to example 11 described in WO2006/133822 has a significantly higher average particle size than the precipitated amorphous Letermovir proposed in the present invention. This indicates that the particle size distribution curve for BXR3GBL is significantly higher than that for the precipitated amorphous Letermovir of the present invention.

A specific method for determining PSD is characterized by the following conditions:

Device: Mastersizer 2000 using dry dispersion

Methodology: according to Fraunhofer; weighed quantity: 0.3-0.4 g

Measurement duration: 20 s

Background time: 6s

Sensitivity reduction limits: 0.5 to 6%

Sample cell: microvolume; fine sieve with balls

Loading speed: 45-55%

Dispersing pressure: 2.5 bar.

Four independent studies were performed and the results were averaged.

14) Determination of purity using gas chromatography

Purity was determined by gas chromatography for 4 batches of precipitated amorphous Letermovir, as well as for a batch of amorphous Letermovir (designated BXR3GBL) prepared in accordance with Example 11 in WO2006/133822. The results of the study are shown in the table below. 24:

Table 24. Determination of purity using gas chromatography

Impurities Lot number or identifying name of Letermovir Besieged Letermovir Letermovir prepared according to example 11 in WO2006/133822 1300698 1300712 1300735 1300750 BXR3GBL 2-Methoxy-5(trifluoromethyl)aniline < 1.5 ppm < 1.5 ppm < 1.5 ppm < 1.5 ppm <1.5 ppm 3-Methoxyaniline < 1.5 ppm < 1.5 ppm < 1.5 ppm < 1.5 ppm 10 ppm Bis-(2chloroethyl)amine < 1.5 ppm < 1.5 ppm < 1.5 ppm < 1.5 ppm <1.5 ppm Mesityl oxide 9 ppm 23 ppm 31 ppm 27 ppm 240 ppm 2-Methoxy-5(trifluoromethyl) isocyanate - - - - 35 ppm

From the results given in table. 24, it can be concluded that the prior art batch of BXR3GBL, which was prepared in accordance with Example 11 described in WO 2006/133822, has a significantly higher content of toxic impurities than the precipitated amorphous Letermovir obtained by the methods proposed in the present invention.

Description of the figures

Fig. 1: Deposition Experiments. No. 1-3: removal of MTBE by distillation using methanol, ethanol and acetonitrile; Letermovir is precipitated by adding it to water. No. 4: removal of MTBE by distillation using acetone; Letermovir is precipitated by adding it to water. No. 5-6; reverse precipitation: water is added to a solution in acetone and acetonitrile, respectively. No. 7-11; modeling the production of roller-dried Letermovir by drum drying using methanol, ethanol, acetonitrile, DCM (dichloromethane) and MTBE as volatile solvents. Reduced yield due to loss of material on the walls of the glass vessel.

Fig. 2: Shown is the XRPD radiograph corresponding to sample no.

-

Claims (8)

11 shown in FIG. 1. Sample 11 was isolated by simulating the production of roller dried Letermovir by drum drying using MTBE as a volatile solvent. The x-ray pattern is typical of an amorphous solid such as Letermovir. All other X-ray diffraction patterns (samples no. 1-10) are essentially the same as the x-ray diffraction pattern of sample no. 11. It is clear that all isolation methods resulted in an amorphous substance (see also XRPD morphology column, Fig. 1). Fig. 3: HPLC chromatogram of isolated Letermovir. Fig. 4: Raman spectrum of amorphous Letermovir. Raman spectroscopy studies were carried out in accordance with the Ph.Eur method. Ed. VI, using Raman spectrometer type Bruker RFS 100/S, laser excitation power: 400 mW, resolution: 2 cm-1, number of scans = 128, acquisition range: 3300 - 0 cm-1, aperture: 5.0 mm, 96-well glass plates, and spectrum processing was performed corrected for a linear baseline with normalization. In fig. Figure 4 shows a comparison of the spectra obtained for solid Letermovir (1) and solubilized Letermovir (2), and their difference from the spectrum of DMSO (3). The results obtained by Raman spectroscopy also confirm that Letermovir is amorphous, which is in agreement with the results obtained by XRPD presented in FIG. 2. Fig. 5: Solubility of amorphous Letermovir in water. Fig. 6: Dependence of Letermovir solubility on pH value. Fig. 7a and 7b: Results of pharmacokinetic study. The absolute bioavailability of Letermovir was studied at a subtherapeutic dose of 30 mg. Fig. 8: a) The stability of a tablet containing 240 mg of Letermovir was studied; b) studied the stability of a tablet containing 60 mg of Letermovir; c) studied the stability of a tablet containing 120 mg of Letermovir. Fig. 9: a) Particle size distribution diagram for a batch of precipitated Letermovir according to the present invention (1300750), showing different profiles obtained at time intervals of approximately 2-3 minutes; b) Particle size distribution diagram for a batch of precipitated Letermovir according to the present invention (1300735), showing different profiles obtained at time intervals of less than 2 minutes; c) Particle size distribution diagram for a batch of Letermovir (designated BXR3GBL) obtained in accordance with Example 11 in WO 2006/133822 A1, showing different profiles obtained at approximately 2 min time intervals. Fig. 10: Results of a stability study of batch 10101001 of precipitated amorphous Letermovir of the present invention at 25° C./60% relative humidity (long-term storage conditions). Fig. 11: Results of a stability study of batch 09041001 of precipitated amorphous Letermovir of the present invention at 25° C./60% relative humidity for 48 months. Fig. 12: Reaction scheme for the preferred synthesis route of Letermovir. The asterisk located in the lower left part before the solvent replacement step 4) indicates the step at which the isolation according to the present invention begins. The diagram shows as an example the most preferred isolation procedure, carried out by replacing the solvent with acetone (4), followed by precipitation, carried out by spraying into water (5). Isolation is then carried out by centrifugation. CLAIM (1) an acidic environment such as enzyme-free artificial gastric juice USP; 1. Powdered Letermovir of formula (I) P I Formula (I), which is in an amorphous state and is suitable for use in solid dosage forms for oral administration, wherein said Letermovir is characterized in that: i) according to a BET (Brunauer-Emmett-Teller) specific surface area study, it has a specific surface area of at least 1 m ² /g and/or ii) according to a particle size distribution study, it has an average value - 39 043692 particle size distribution of not more than 10 microns, which is obtained by a precipitation method, including the preparation of a solution of Letermovir in water-miscible solvents selected from acetone or acetonitrile, and the precipitation of said letermovir from the solution with stirring in excess water, used as antisolvent, followed by filtration or centrifugation to obtain the specified powdered amorphous Letermovir. (2) a buffer having a pH value of 4.5; and (3) a buffer having a pH value of 6.8 or enzyme-free artificial gastric juice USP. 2. A solid pharmaceutical preparation for oral administration containing powdered letermovir in an amorphous state according to claim 1 and one or more pharmaceutically acceptable excipients. 3. The solid pharmaceutical preparation according to claim 2, further containing povidone, croscarmellose sodium salt, microcrystalline cellulose, colloidal anhydrous silicon dioxide and magnesium stearate. 4. Solid pharmaceutical preparation according to claim 3, in which the specified Letermovir in an amorphous state is contained in an amount from 30.0 to 50.0% (wt./wt.), the specified povidone is contained in an amount from 2.0 to 10.0 % (wt./wt.), the specified sodium salt of croscarmellose is contained in an amount from 2.0 to 10.0% (wt./wt.), the specified microcrystalline cellulose is contained in an amount from 20.0 to 50.0% (wt./wt.) ./wt.), said colloidal anhydrous silicon dioxide is contained in an amount of from 0.5 to 5.0% (wt./wt.), and said magnesium stearate is contained in an amount of from 0.1 to 5.0% (wt./wt.) wt.). 5. A solid pharmaceutical preparation according to claims 2-4, which is effective in ensuring the absolute bioavailability of Letermovir 70±30% if it is administered orally as part of the specified preparation containing at least 5 mg of Letermovir in an amorphous state. 6. Solid pharmaceutical preparation according to any one of claims 2-4, in which Letermovir in an amorphous state is characterized by a degree of dissolution of > 50% no later than 30 minutes, preferably > 60% no later than 30 minutes, more preferably > 70 % no later than 30 minutes, even more preferably >80% no later than 30 minutes, most preferably >90% no later than 30 minutes if the dissolution of Letermovir in the amorphous state is studied using the Ph.Eur method. 2.9.3, Apparatus 2, at a blade rotation speed of 50 rpm, at 37.0 ± 0.5 ° C in 1000 ml of 0.1 N medium. HCl/0.2% sodium lauryl sulfate solution and examined by reverse phase HPLC for 30 minutes as follows: HPLC conditions: Column: Waters Symmetry Nucleosil 100 C18, 40 mmx4.0 mm, 10 µm Detection wavelength: 256 nm Approximately 4 min Duration of the experiment: Approximate time: 1.3 min hold: Column temperature: 40°C Injected volume: 20 µl Flow rate: 1.5ml/min Mobile phase: pH 4.0 buffer/acetonitrile; 55/45 rev/rev 7. Solid pharmaceutical preparation according to any one of claims 2 to 6, where said solid pharmaceutical preparation is an immediate release preparation, characterized in that at least 85% of Letermovir in the amorphous state dissolves no later than after 30 minutes when using USP Apparatus I at 100 rpm or USP Apparatus II at 50 rpm in each of the following media of 900 mL or less: 8. The solid pharmaceutical preparation according to any one of claims 2 to 7, wherein said Letermovir in the amorphous state has chemical stability for at least 36 months when stored at room temperature 25°C and relative humidity 60%, if determined using Reverse phase HPLC using gradient mode as follows: HPLC conditions: Column: Intertsil ODS III, 5 µm, or equivalent Solvent: acetonitrile/0.1 N. HCl solution; 3+7 (rev/rev) Eluent: A: water, pH 2.40; B: acetonitrile Detection wavelength: 235 nm Column temperature: 40°C Injected volume: 15 µl Flow rate: 1.0ml/min Experiment duration: 30 min -