MannitolQualityChecker

Вот полный пакет утилиты **`MannitolQualityChecker`**.

Эта утилита предназначена для контроля качества субстанции и готовых лекарственных форм **Маннита** (сахарный спирт, используемый как наполнитель в таблетках, растворитель для инъекций и диуретик). Ключевые особенности: Маннит является кристаллическим веществом с полиморфизмом. Критически важны контроль кристаллической формы (альфа- или бета-маннит), содержания примесей (сорбитол, глюкоза, другие сахара), остаточных растворителей синтеза (вода, этанол) и профиля растворения. Препарат применяется как парентерально, так и перорально, поэтому требования к чистоте высоки.

---

### 1. Исходный код (`MannitolQualityChecker.cs`)

```csharp
using System;
using System.Globalization;
using System.IO;
using System.Collections.Generic;
using System.Linq;
using Newtonsoft.Json;

public class Record
{
    public string BatchNumber { get; set; }
    public double Assay_Percent { get; set; } // Content on dried basis
    public double Melting_Point_Min { get; set; }
    public double Melting_Point_Max { get; set; }
    
    // Impurities
    public double Sorbitol_Percent { get; set; } // Main related substance
    public double Glucose_Percent { get; set; } // Degradation product
    public double Total_Impurities_Percent { get; set; }
    
    public double Loss_On_Drying_Percent { get; set; }
    public double Residual_Solvent_Ethanol_ppm { get; set; }
    public double Residual_Solvent_Water_ppm { get; set; } // Often high for mannitol
    public double Heavy_Metals_ppm { get; set; }
    public double Sulfated_Ash_Percent { get; set; }
    
    // Dissolution parameters
    public double Dissolution_30min_Percent { get; set; }
    public double Dissolution_60min_Percent { get; set; }
    
    public double Weight_Variation_RSD { get; set; }
    public double Friability_Percent { get; set; }
    
    public double Microbial_Count_TAMC { get; set; }
    public double Microbial_Count_TYMC { get; set; }
    public double EColi_Detected { get; set; }
    public double Salmonella_Detected { get; set; }
}

public class AppResult
{
    public string ErrorMessage { get; set; } = "";
    public object Result { get; set; }
}

class Program
{
    const string DEFAULT_INPUT = "input.csv";

    static void Main(string[] args)
    {
        if (args.Length == 0)
        {
            RunWithFiles(inputPath: null, outputPath: null);
            return;
        }

        if (args.Length == 2)
        {
            RunWithFiles(args[0], args[1]);
            return;
        }

        PrintHello();
    }

    static void RunWithFiles(string inputPath, string outputPath)
    {
        AppResult response = new AppResult();
        try
        {
            var records = LoadData(inputPath);
            if (records.Count == 0)
            {
                records = GetDemoData();
            }

            var results = new List<object>();
            foreach (var record in records)
            {
                var result = Evaluate(record);

                results.Add(new
                {
                    result.BatchNumber,
                    Identity_And_Strength = new
                    {
                        Assay = new { Measured = result.Assay_Percent, Min = 98.0, Max = 102.0, Ok = result.AssayOk, Unit = "%", Note = "Dried basis" },
                        Melting_Range = new { Min = result.Melting_Point_Min, Max = result.Melting_Point_Max, ExpectedMin = 165, ExpectedMax = 170, Ok = result.Mp_Ok, Unit = "°C", Note = "Decomposition" }
                    },
                    Impurities = new
                    {
                        Sorbitol = new { Measured = result.Sorbitol_Percent, Max = 0.5, Ok = result.SorbitolOk, Unit = "%" },
                        Glucose = new { Measured = result.Glucose_Percent, Max = 0.5, Ok = result.GlucoseOk, Unit = "%" },
                        Total_Impurities = new { Measured = result.Total_Impurities_Percent, Max = 1.0, Ok = result.TotalImpOk, Unit = "%" }
                    },
                    PhysicoChemical = new
                    {
                        Loss_On_Drying = new { Measured = result.Loss_On_Drying_Percent, Max = 0.5, Ok = result.LOD_Ok, Unit = "%" },
                        Sulfated_Ash = new { Measured = result.Sulfated_Ash_Percent, Max = 0.1, Ok = result.Ash_Ok, Unit = "%" },
                        Heavy_Metals = new { Measured = result.Heavy_Metals_ppm, Max = 10, Ok = result.HM_Ok, Unit = "ppm" }
                    },
                    Residual_Solvents = new
                    {
                        Ethanol = new { Measured = result.Residual_Solvent_Ethanol_ppm, Max = 5000, Ok = result.EtOH_Ok, Unit = "ppm" },
                        Water = new { Measured = result.Residual_Solvent_Water_ppm, Max = 10000, Ok = result.WaterOk, Unit = "ppm", Note = "Often higher limit for hygroscopic sugars" }
                    },
                    Performance = new
                    {
                        Dissolution_Profile = result.Dissolution_30min_Percent > 0 ? new
                        {
                            Time_30min = new { Measured = result.Dissolution_30min_Percent, Min = 80.0, Ok = result.Diss30_Ok, Unit = "%" },
                            Time_60min = new { Measured = result.Dissolution_60min_Percent, Min = 85.0, Ok = result.Diss60_Ok, Unit = "%" }
                        } : null,
                        Weight_Variation_RSD = result.Weight_Variation_RSD > 0 ? new { Measured = result.Weight_Variation_RSD, Max = 5.0, Ok = result.RSD_Ok, Unit = "%" } : null
                    },
                    Safety = new
                    {
                        Microbiology = new
                        {
                            TAMC = new { Measured = result.Microbial_Count_TAMC, Max = 1000, Ok = result.TAMC_Ok, Unit = "CFU/g" },
                            TYMC = new { Measured = result.Microbial_Count_TYMC, Max = 100, Ok = result.TYMC_Ok, Unit = "CFU/g" },
                            EColi = new { Detected = record.EColi_Detected > 0, Ok = result.EColi_Ok, Critical = true },
                            Salmonella = new { Detected = record.Salmonella_Detected > 0, Ok = result.Salmonella_Ok, Critical = true }
                        }
                    },
                    AllWithinLimits = result.AllOk,
                    Recommendation = result.Recommendation
                });
            }

            response.Result = new
            {
                Results = results,
                Input = records,
                Disclaimer = "Оценка Маннита. Критично: сорбитол/глюкоза, профиль растворения. Результат не заменяет официальную сертификацию.",
                DisclaimerEN = "Assessment of Mannitol. Critical: sorbitol/glucose, dissolution profile. Result does not replace official certification."
            };
        }
        catch (Exception ex)
        {
            response.ErrorMessage = ex.Message;
        }

        string json = JsonConvert.SerializeObject(response, Formatting.Indented);
        if (string.IsNullOrEmpty(outputPath))
        {
            Console.WriteLine(json);
        }
        else
        {
            File.WriteAllText(outputPath, json);
            Console.WriteLine($"Результат сохранён в: {outputPath}");
        }
    }

    static List<Record> LoadData(string csvPath = null)
    {
        var ni = CultureInfo.InvariantCulture;
        var records = new List<Record>();

        string path = csvPath ?? DEFAULT_INPUT;
        if (File.Exists(path))
        {
            var lines = File.ReadAllLines(path);
            if (lines.Length > 1)
            {
                var line = lines[1].Trim();
                if (!string.IsNullOrEmpty(line))
                {
                    var parts = line.Split(',');
                    if (parts.Length >= 19)
                    {
                        records.Add(new Record
                        {
                            BatchNumber = parts[0].Trim(),
                            Assay_Percent = double.Parse(parts[1].Trim(), ni),
                            Melting_Point_Min = double.Parse(parts[2].Trim(), ni),
                            Melting_Point_Max = double.Parse(parts[3].Trim(), ni),
                            Sorbitol_Percent = double.Parse(parts[4].Trim(), ni),
                            Glucose_Percent = double.Parse(parts[5].Trim(), ni),
                            Total_Impurities_Percent = double.Parse(parts[6].Trim(), ni),
                            Loss_On_Drying_Percent = double.Parse(parts[7].Trim(), ni),
                            Residual_Solvent_Ethanol_ppm = double.Parse(parts[8].Trim(), ni),
                            Residual_Solvent_Water_ppm = double.Parse(parts[9].Trim(), ni),
                            Heavy_Metals_ppm = double.Parse(parts[10].Trim(), ni),
                            Sulfated_Ash_Percent = double.Parse(parts[11].Trim(), ni),
                            Dissolution_30min_Percent = parts.Length > 12 && !string.IsNullOrEmpty(parts[12]) ? double.Parse(parts[12].Trim(), ni) : 0.0,
                            Dissolution_60min_Percent = parts.Length > 13 && !string.IsNullOrEmpty(parts[13]) ? double.Parse(parts[13].Trim(), ni) : 0.0,
                            Weight_Variation_RSD = parts.Length > 14 && !string.IsNullOrEmpty(parts[14]) ? double.Parse(parts[14].Trim(), ni) : 0.0,
                            Friability_Percent = parts.Length > 15 && !string.IsNullOrEmpty(parts[15]) ? double.Parse(parts[15].Trim(), ni) : 0.0,
                            Microbial_Count_TAMC = double.Parse(parts[16].Trim(), ni),
                            Microbial_Count_TYMC = parts.Length > 17 ? double.Parse(parts[17].Trim(), ni) : 0,
                            EColi_Detected = parts.Length > 18 ? double.Parse(parts[18].Trim(), ni) : 0,
                            Salmonella_Detected = parts.Length > 19 ? double.Parse(parts[19].Trim(), ni) : 0
                        });
                    }
                }
            }
        }
        return records;
    }

    static List<Record> GetDemoData()
    {
        return new List<Record>
        {
            new Record
            {
                BatchNumber = "MAN-SUB-2026-001",
                Assay_Percent = 99.5,
                Melting_Point_Min = 166,
                Melting_Point_Max = 169,
                Sorbitol_Percent = 0.2,
                Glucose_Percent = 0.1,
                Total_Impurities_Percent = 0.3,
                Loss_On_Drying_Percent = 0.3,
                Residual_Solvent_Ethanol_ppm = 800,
                Residual_Solvent_Water_ppm = 2000,
                Heavy_Metals_ppm = 5,
                Sulfated_Ash_Percent = 0.05,
                Dissolution_30min_Percent = 0.0, // Substance
                Dissolution_60min_Percent = 0.0,
                Weight_Variation_RSD = 0.0,
                Friability_Percent = 0.0,
                Microbial_Count_TAMC = 20,
                Microbial_Count_TYMC = 5,
                EColi_Detected = 0,
                Salmonella_Detected = 0
            }
        };
    }

    // ИСПОЛЬЗОВАНИЕ ИМЕНОВАННОГО КОРТЕЖА
    static (
        string BatchNumber,
        double Assay_Percent, bool AssayOk,
        double Melting_Point_Min, double Melting_Point_Max, bool Mp_Ok,
        double Sorbitol_Percent, bool SorbitolOk,
        double Glucose_Percent, bool GlucoseOk,
        double Total_Impurities_Percent, bool TotalImpOk,
        double Loss_On_Drying_Percent, bool LOD_Ok,
        double Residual_Solvent_Ethanol_ppm, bool EtOH_Ok,
        double Residual_Solvent_Water_ppm, bool WaterOk,
        double Heavy_Metals_ppm, bool HM_Ok,
        double Sulfated_Ash_Percent, bool Ash_Ok,
        double Dissolution_30min_Percent, bool Diss30_Ok,
        double Dissolution_60min_Percent, bool Diss60_Ok,
        double Weight_Variation_RSD, bool RSD_Ok,
        double Microbial_Count_TAMC, bool TAMC_Ok,
        double Microbial_Count_TYMC, bool TYMC_Ok,
        bool EColi_Ok,
        bool Salmonella_Ok,
        bool AllOk,
        string Recommendation
    ) Evaluate(Record r)
    {
        // Identity & Strength
        bool assayOk = r.Assay_Percent >= 98.0 && r.Assay_Percent <= 102.0;
        bool mp_Ok = r.Melting_Point_Min >= 165 && r.Melting_Point_Max <= 170;

        // Impurities
        bool sorbitolOk = r.Sorbitol_Percent <= 0.5;
        bool glucoseOk = r.Glucose_Percent <= 0.5;
        bool totalImpOk = r.Total_Impurities_Percent <= 1.0;

        // Physicochemical
        bool lodOk = r.Loss_On_Drying_Percent <= 0.5;
        bool ashOk = r.Sulfated_Ash_Percent <= 0.1;
        bool hmOk = r.Heavy_Metals_ppm <= 10;

        // Solvents
        bool etohOk = r.Residual_Solvent_Ethanol_ppm <= 5000;
        bool waterOk = r.Residual_Solvent_Water_ppm <= 10000;

        // Dissolution
        bool diss30Ok = r.Dissolution_30min_Percent == 0 || r.Dissolution_30min_Percent >= 80.0;
        bool diss60Ok = r.Dissolution_60min_Percent == 0 || r.Dissolution_60min_Percent >= 85.0;

        bool rsdOk = r.Weight_Variation_RSD == 0 || r.Weight_Variation_RSD <= 5.0;

        // Safety
        bool tamcOk = r.Microbial_Count_TAMC <= 1000;
        bool tymcOk = r.Microbial_Count_TYMC <= 100;
        bool eColiOk = r.EColi_Detected == 0;
        bool salmonellaOk = r.Salmonella_Detected == 0;

        bool allOk = assayOk && mp_Ok && sorbitolOk && glucoseOk && totalImpOk &&
                     lodOk && ashOk && hmOk && etohOk && waterOk &&
                     diss30Ok && diss60Ok && rsdOk &&
                     tamcOk && tymcOk && eColiOk && salmonellaOk;

        var issues = new List<string>();
        if (!assayOk) issues.Add($"Assay: {r.Assay_Percent:F1}% outside [98-102]");
        if (!sorbitolOk) issues.Add($"Sorbitol: {r.Sorbitol_Percent:F2}% > 0.5%");
        if (!glucoseOk) issues.Add($"Glucose: {r.Glucose_Percent:F2}% > 0.5%");
        if (!totalImpOk) issues.Add($"Total Impurities: {r.Total_Impurities_Percent:F2}% > 1.0%");
        if (!waterOk) issues.Add($"Water: {r.Residual_Solvent_Water_ppm:F0} ppm > 10000 ppm");
        if (!diss30Ok && r.Dissolution_30min_Percent > 0) issues.Add($"Dissolution 30min: {r.Dissolution_30min_Percent:F1}% < 80%");
        
        string recommendation = allOk
            ? "Mannitol batch complies with Ph. Eur. / USP specifications."
            : $"OOS detected. Issues: {string.Join("; ", issues)}";

        return (
            BatchNumber: r.BatchNumber,
            Assay_Percent: r.Assay_Percent,
            AssayOk: assayOk,
            Melting_Point_Min: r.Melting_Point_Min,
            Melting_Point_Max: r.Melting_Point_Max,
            Mp_Ok: mp_Ok,
            Sorbitol_Percent: r.Sorbitol_Percent,
            SorbitolOk: sorbitolOk,
            Glucose_Percent: r.Glucose_Percent,
            GlucoseOk: glucoseOk,
            Total_Impurities_Percent: r.Total_Impurities_Percent,
            TotalImpOk: totalImpOk,
            Loss_On_Drying_Percent: r.Loss_On_Drying_Percent,
            LOD_Ok: lodOk,
            Residual_Solvent_Ethanol_ppm: r.Residual_Solvent_Ethanol_ppm,
            EtOH_Ok: etohOk,
            Residual_Solvent_Water_ppm: r.Residual_Solvent_Water_ppm,
            WaterOk: waterOk,
            Heavy_Metals_ppm: r.Heavy_Metals_ppm,
            HM_Ok: hmOk,
            Sulfated_Ash_Percent: r.Sulfated_Ash_Percent,
            Ash_Ok: ashOk,
            Dissolution_30min_Percent: r.Dissolution_30min_Percent,
            Diss30_Ok: diss30Ok,
            Dissolution_60min_Percent: r.Dissolution_60min_Percent,
            Diss60_Ok: diss60Ok,
            Weight_Variation_RSD: r.Weight_Variation_RSD,
            RSD_Ok: rsdOk,
            Microbial_Count_TAMC: r.Microbial_Count_TAMC,
            TAMC_Ok: tamcOk,
            Microbial_Count_TYMC: r.Microbial_Count_TYMC,
            TYMC_Ok: tymcOk,
            EColi_Ok: eColiOk,
            Salmonella_Ok: salmonellaOk,
            AllOk: allOk,
            Recommendation: recommendation
        );
    }

    static void PrintHello()
    {
        string exeName = Path.GetFileName(System.Reflection.Assembly.GetExecutingAssembly().Location);
        Console.WriteLine("Mannitol Quality Checker — Сахарный спирт (Ph. Eur., USP)");
        Console.WriteLine("");
        Console.WriteLine("ℹ️  Утилита проверяет содержание, сорбитол/глюкозу, воду, профиль растворения.");
        Console.WriteLine("ℹ️  Не использует машинное обучение — только правила.");
        Console.WriteLine("⚠️  КРИТИЧНО! Сорбитол ≤0.5%. Глюкоза ≤0.5%. Вода ≤10000 ppm!");
        Console.WriteLine("");
        Console.WriteLine("Использование:");
        Console.WriteLine($"  {exeName}                            → демо-режим");
        Console.WriteLine($"  {exeName} input.csv output.json      → оценка данных");
        Console.WriteLine("");
        Console.WriteLine("Формат input.csv:");
        Console.WriteLine("BatchNumber,Assay_Percent,Melting_Point_Min,Melting_Point_Max,Sorbitol_Percent,Glucose_Percent,Total_Impurities_Percent,Loss_On_Drying_Percent,Residual_Solvent_Ethanol_ppm,Residual_Solvent_Water_ppm,Heavy_Metals_ppm,Sulfated_Ash_Percent,Dissolution_30min_Percent,Dissolution_60min_Percent,Weight_Variation_RSD,Friability_Percent,Microbial_Count_TAMC,Microbial_Count_TYMC,EColi_Detected,Salmonella_Detected");
        Console.WriteLine("");
        Console.WriteLine(@"Пример:");
        Console.WriteLine(@"MAN-SUB-2026-001,99.5,166,169,0.2,0.1,0.3,0.3,800,2000,5,0.05,0.0,0.0,0.0,0.0,20,5,0,0");
    }
}
```

---

### 2. Входные данные (`input.csv`)

```csv
BatchNumber,Assay_Percent,Melting_Point_Min,Melting_Point_Max,Sorbitol_Percent,Glucose_Percent,Total_Impurities_Percent,Loss_On_Drying_Percent,Residual_Solvent_Ethanol_ppm,Residual_Solvent_Water_ppm,Heavy_Metals_ppm,Sulfated_Ash_Percent,Dissolution_30min_Percent,Dissolution_60min_Percent,Weight_Variation_RSD,Friability_Percent,Microbial_Count_TAMC,Microbial_Count_TYMC,EColi_Detected,Salmonella_Detected
MAN-SUB-2026-001,99.5,166,169,0.2,0.1,0.3,0.3,800,2000,5,0.05,0.0,0.0,0.0,0.0,20,5,0,0
```

---

### 3. Описание (`MannitolQualityChecker.description.txt`)

```text
Mannitol Quality Checker — Сахарный спирт (Ph. Eur., USP)

ℹ️  Утилита проверяет содержание, сорбитол/глюкозу, воду, профиль растворения.
ℹ️  Не использует машинное обучение — только правила.
⚠️  КРИТИЧНО! Сорбитол ≤0.5%. Глюкоза ≤0.5%. Вода ≤10000 ppm!

Использование:
  MannitolQualityChecker.exe                            → демо-режим
  MannitolQualityChecker.exe input.csv output.json      → оценка данных

Формат input.csv:
BatchNumber,Assay_Percent,Melting_Point_Min,Melting_Point_Max,Sorbitol_Percent,Glucose_Percent,Total_Impurities_Percent,Loss_On_Drying_Percent,Residual_Solvent_Ethanol_ppm,Residual_Solvent_Water_ppm,Heavy_Metals_ppm,Sulfated_Ash_Percent,Dissolution_30min_Percent,Dissolution_60min_Percent,Weight_Variation_RSD,Friability_Percent,Microbial_Count_TAMC,Microbial_Count_TYMC,EColi_Detected,Salmonella_Detected

Пример:
MAN-SUB-2026-001,99.5,166,169,0.2,0.1,0.3,0.3,800,2000,5,0.05,0.0,0.0,0.0,0.0,20,5,0,0

— ЗАЧЕМ ЭТО НУЖНО?
Маннит — сахарный спирт, используемый как наполнитель в таблетках, растворитель для инъекций и осмотический диуретик:
• Примеси синтеза: Основными примесями являются сорбитол (изомер) и глюкоза (продукт восстановления маннозы). Их контроль критичен для обеспечения чистоты вещества.
• Влажность: Маннит гигроскопичен. Контроль воды важен для стабильности и технологических свойств (текусть порошка). Лимиты могут быть выше, чем для других веществ (до 1%).
• Синтез часто включает использование этанола и воды. Лимиты остаточных растворителей строги.
• Профиль растворения важен для обеспечения быстрой биодоступности.
⚠️ КРИТИЧЕСКИ ВАЖНО:
• Содержание: 98–102%
• Температура плавления: 165–170°C (с разложением)
• Сорбитол: ≤ 0.5%
• Глюкоза: ≤ 0.5%
• Сумма примесей: ≤ 1.0%
• Вода: ≤ 1.0% (или 10000 ppm)
• Этанол: ≤ 5000 ppm
• Тяжелые металлы: ≤ 10 ppm
• Растворение: ≥ 80% за 30 минут, ≥ 85% за 60 минут
• Микробиология: стандартные лимиты
⚠️ Особенность: Утилита адаптирована под проверку профиля растворения. Если данные по растворению отсутствуют (0), проверка пропускается (для субстанции). Для готовых форм отклонение от профиля растворения является критическим дефектом. Контроль сорбитола и глюкозы является приоритетом безопасности из-за их потенциального влияния на осмолярность и стабильность препарата.