Chrono-Modulated Pulsatile Drug Delivery System of Hydralazine HCL An Effective Treatment Method for Hypertension

• The therapeutic effectiveness of many drugs is significantly influenced by the body's circadian rhythms, especially in conditions such as hypertension, asthma, and arthritis. Among these, hypertension demonstrates a well-documented circadian pattern, characterized by early morning surges in blood pressure that elevate the risk of cardiovascular events, including stroke and myocardial infarction. Conventional dosage forms often fail to align drug release with these critical time windows, potentially reducing therapeutic efficacy and increasing side effects.
• With rapid advancements in drug delivery technologies, significant attention has been redirected from new drug discovery toward optimizing the delivery of existing molecules. This transition arises due to the numerous hurdles, regulatory and economic associated with the traditional drug discovery process ^[1]_.
• Traditional drug delivery primarily aims to ensure predictable systemic absorption of active pharmaceutical ingredients (APIs). Controlled-release systems were developed to maintain drug concentrations within the therapeutic window over extended periods, thereby reducing dosing frequency and improving compliance. These systems often follow a zero-order release pattern, offering constant plasma levels.
• However, biological systems do not adhere to zero-order dynamics. Drug efficacy and toxicity are closely linked to the body's circadian rhythms, which follow a 24-hour cycle. Diseases such as asthma, hypertension, arthritis, and cardiovascular conditions exhibit time-dependent variations in symptoms and severity ^[2].
• This discrepancy led to the emergence of chrono pharmaceutics, a field that focuses on designing drug delivery systems to release drugs in harmony with biological rhythms for optimized therapy ^[3].
• Limitations of Conventional Sustained Release Systems

Although widely used, constant-rate drug delivery systems are not suitable for all drugs or disease states. Limitations include:

• First-pass metabolism: Gradual release may result in substantial metabolic degradation, reducing bioavailability.
• Short half-life drugs: Require frequent dosing to maintain therapeutic levels, leading to poor compliance.
• Tolerance: Constant drug levels can lead to decreased drug effect over time.
• Chronic toxicity: Continuous exposure, especially in chronic diseases like diabetes, can result in cumulative organ damage ^[4].
• Loss of therapeutic flexibility: Static release patterns do not adapt to diurnal variations in disease or physiology.

• Pulsatile Drug Delivery Systems (PDDS)

Pulsatile drug delivery systems (PDDS) offer a promising solution by introducing a programmed lag phase followed by rapid drug release, thus synchronizing drug plasma concentration peaks with the time of symptom exacerbation. These systems are particularly advantageous for drugs with short half-lives or those requiring chronotherapeutic administrations.

• Types of PDDS

• Time-Controlled Systems: Designed with a lag phase, followed by a burst release.
• PH-Sensitive Systems: Utilize enteric coatings that dissolve at specific gastrointestinal pH.
• Microbial-Triggered Systems: Exploit enzymes in the colon flora for targeted drug release.

• Chronotherapy and Disease States

Certain diseases require time-aligned therapy, including:

• Asthma: Symptoms worsen at night; PDDS can release bronchodilators in early morning hours.
• Cardiovascular Diseases: Heart attacks and strokes are more common in early morning.
• Rheumatoid Arthritis: Morning stiffness is prevalent; PDDS can release NSAIDs pre-dawn.
• Peptic Ulcers: Acid secretion peaks during the night.

• Advantages of PDDS

• Predictable and short gastric residence time
• Minimal inter- and intra-subject variability
• Reduced side effects and better tolerability
• Improved drug bioavailability and stability
• No dose dumping risk
• Increased patient compliance
• Patent life extension and commercial competitiveness

• Challenges and Limitations

• Complex manufacturing processes
• High production cost
• Need for skilled personnel and advanced technology
• Multiple formulation variables require optimization
• Difficulty in ensuring batch reproducibility and scalability

• Hydralazine hydrochloride, a direct-acting vasodilator frequently used to manage hypertension, is an ideal candidate for pulsatile delivery due to its short biological half-life and the need for frequent dosing. This study aims to develop and evaluate a core-in-cup PDDS for Hydralazine HCl designed to release the drug following a predefined lag time, thereby targeting the early-morning rise in blood pressure.
• The proposed delivery system consists of a core tablet containing Hydralazine HCl, encased within a cup-shaped impermeable barrier made of cellulose acetate propionate, and sealed with a hydrophilic, swellable polymeric layer composed of Sodium Alginate, Hydroxypropyl methyl cellulose (HPMC) K4M, and Sodium carboxy methyl cellulose (SCMC). Each component is selected for its role in modulating the lag phase and subsequent drug release.
• The primary objective of this research is to optimize the formulation parameters and evaluate the system’s physicochemical characteristics, in-vitro release profile, and potential efficacy as a chronotherapeutic intervention for managing morning hypertension.

Objective

Need for the Study

• The development of oral controlled-release drug delivery systems offers several advantages over conventional immediate-release formulations. These advanced systems are designed to release drugs at a controlled and predetermined rate, thereby maintaining therapeutically effective concentrations in systemic circulation for extended periods. However, in certain therapeutic areas, particularly chronotherapy, a pulsatile drug release pattern where the drug is released following a defined lag time can provide significant therapeutic benefits.
• Chronopharmacotherapy, which aligns drug administration with the body's circadian rhythms, is gaining considerable global attention. Numerous diseases such as asthma, hypertension, and rheumatoid arthritis exhibit circadian variation in their symptoms, necessitating a time-specific drug release for maximum therapeutic efficacy. For instance, inflammatory conditions associated with morning stiffness, nocturnal asthma, and early morning cardiac events require drug levels to peak during those times. Immediate-release formulations may not be effective in such scenarios, particularly if symptoms manifest during night or early morning hours.
• Although modified-release formulations with zero-order kinetics aim to maintain constant plasma drug levels throughout the day, they often fail to match the time-dependent pathophysiology of many diseases. This may lead to suboptimal therapeutic effects during symptom peaks and unnecessary drug exposure at other times, increasing the risk of adverse effects. To optimize efficacy, safety, and patient compliance, Chronopharmaceutical drug delivery systems especially Time-Controlled Drug Delivery Systems (TCDDS) present a promising solution.
• Hydralazine Hydrochloride is a vasodilator primarily used in the management of cardiovascular diseases such as hypertension, myocardial infarction, congestive heart failure, and for cardiovascular risk prophylaxis. However, its conventional dosage forms suffer from a short half-life (~6 hours), necessitating multiple daily dosing (2–3 times daily), which can compromise patient compliance and therapeutic effectiveness. Cardiovascular events such as increased blood pressure and heart attacks often occur in the early morning hours, indicating the need for a drug delivery system that ensures drug availability during these critical periods.
• Therefore, this study aims to design and evaluate a chrono-modulated pulsatile drug delivery system of Hydralazine HCL using the direct compression method. The proposed system is expected to offer the following advantages:

• Synchronization of drug release with the body's circadian rhythms and disease activity
• Minimized side effects due to targeted release
• Reduced dosing frequency and dosage size
• Improved patient adherence to therapy
• Lower overall treatment cost due to fewer dosage units required

MATERIALS AND METHODS:

MATERIALS:

Hydralazine hydrochloride was obtained as a gift sample from a certified pharmaceutical manufacturer. Excipients used include Microcrystalline Cellulose (MCC), Lactose, and Magnesium Stearate for core tablet formulation. Cellulose acetate propionate was used as the hydrophobic polymer for the impermeable cup, and Sodium Alginate, Hydroxypropyl Methylcellulose (HPMC K4M), and Sodium Carboxymethylcellulose (Sodium CMC) were used as hydrophilic polymers for the top layer. All other reagents and solvents used were of analytical grade.

Evaluation of Hydralazine HCL:

Preparation of Calibration Curve in Methanol

An accurately weighted amount of Hydralazine HCL equivalent to 100 mg was dissolved in 100ml of Methanol. A series of standard solution containing Beer’s Lambert’s range of concentration from 5 to 25 µ g/ml of Hydralazine HCL were prepared and absorbance was measured at 260 nm against blank reagent. All spectral absorbance was measured on T80 PG instrument limited, UV- VIS spectrophotometer.

Preparation of Calibration Curve in 6.8 pH phosphate buffer

An accurately weighted amount of Hydralazine HCL equivalent to 100 mg was dissolved in small volume of methanol, in 100 ml volumetric flask and the volume was adjusted to 100 ml with 6.8 pH phosphate buffer and further dilution were made with 6.8 pH phosphate buffer. A series of standard solution containing Beer’s Lambert’s range of concentration from 5 to 25 µ g/ml of Hydralazine HCL potassium were prepared and absorbance was measured at 260 nm against reagent blank. All spectral absorbance was measured on T80 PG instrument limited, UV-VIS spectrophotometer.

Preparation of Core Tablets

Core tablets containing Hydralazine HCl were prepared by direct compression using MCC and lactose as diluents and magnesium stearate as a lubricant. The blend was evaluated for micromeritic properties before compression. Tablets were compressed using a single-punch tablet press to obtain tablets of average thickness 3.6–3.7 mm and hardness 3.4–3.8 kg/cm².

Preparation of Core-in-Cup Tablets

The core-in-cup system was prepared in three steps:

1. Formation of the Cup: A calculated quantity of cellulose acetate propionate was filled into a die cavity and lightly compressed to form the base and side wall of the cup.
2. Insertion of the Core: The pre-compressed core tablet was placed at the center of the cup.
3. Application of Top Layer: A hydrophilic polymer (Sodium Alginate, HPMC K4M, or Sodium CMC) was added on top and compressed to form the final core-in-cup tablet.

Fig 1: Core Tablet of Hydralazine HCL

Evaluation of Powder Blend and Tablets:

The powder blend was evaluated for bulk density, tapped density, angle of repose, and Carr's index. Finished tablets were assessed for hardness, thickness, weight variation, friability, and drug content uniformity as per pharmacopeial standards.

Pre-compression parameters were evaluated as follows:

• Angle of Repose (Fixed funnel method)

Angle of repose is defined as maximum angle possible between the surface of the pile of powder and the horizontal plane. The friction force in a loose powder can be measured by the angle of repose (θ). It is an indicative of the flow properties of the powder. The angle of repose is calculated by using fixed funnel method. In this method the funnel was fixed to a stand at definite height (h). The graph paper was placed on a flat horizontal surface. Then powder blend was allowed to fall freely on the paper through the funnel, until the apex of the conical pile just touches the tip of the funnel. The height and radius of pile was noted and from this angle of repose was determined with the help of given formula,

tan (θ)= h/ r

θ= tan^-1 (h / r)

• Bulk Density

 Bulk density is the ratio of total mass of powder to the bulk volume of powder. It was measured by pouring the accurately weighed 2g of powder blend (passed through 20 mesh sieve) was placed in a 10ml graduated measuring cylinder. And then initial volume was observed, this initial volume is called as bulk volume. From this the bulk density was calculated by using the following formula.

Bulk-density ? Mass of the powder/Bulk volume.

• Tapped Density

Tapped density is the ratio of total mass of powder to the tapped volume of powder. Accurately weighed amount of powder blend was placed in a measuring cylinder and the volume was measured by tapping of powder for 500 times and the tapped volume was noted. The tapped density was calculated by using following formula.

Tapped-density ? Mass of the powder/Tapped volume.

• Carr’s Index

Compressibility index is indicates the powder flow properties. It is expressed in percentage. Compressibility index is based on the bulk density and tapped density; the percentage compressibility of the powder blend was determined by using the following formula.

Carrs Index ? (Tapped-density-Bulk density/Tapped density) x 100

• Hausner’s Ratio

Hausners ratio is an indirect index of ease of powder flow. It was calculated by the following formula

Hausner’s ratio = Tapped density/ Bulk density

Post-compression parameters included:

• Tablet Thickness and Diameter (Vernier caliper)

The thickness of the tablets was determined by using Digital vernier Calipers. Thickness mainly depends upon the die filling, physical properties of material to be compressed under compression force. Three tablets were randomly taken from each formulation, mean and standard deviation values were calculated. It is expressed in mm.

• Hardness (Monsanto hardness tester)

The Monsanto hardness tester was used to determine the tablet hardness. The tablet was held between a fixed and moving jaw. Scale was adjusted to zero load was gradually increased until the tablet fractured. The value of the load at that point gives a measure of hardness of the tablet. Three tablets were randomly taken from each formulation, mean and standard deviation values were calculated. It is expressed in kg/cm²

• Weight Variation (Digital balance)

The weight variation test was performed as per I.P. Twenty tablets were randomly selected from each batch and individually weighed. And then average weight was calculated from the total weight of all tablets. The individual weights were compared with the average weight. The tablets passes the test for weight variation test if no more than two tablets are outside the percentage limit and if no tablet differs by more than two times the percentage limit.

• Friability (Roche friabilator)

The friability test for tablets was performed to assess the effect of abrasion and shocks. Roche friabilator was used for the percent friability of the tablets. This device subjects the tablet to the combined effect of abrasion and shock in a plastic chamber revolving at 25 rpm and dropping a tablet at a height of 6 inches in each revolution. Pre-weighted sample of tablets was placed in the friabilator and were subjected to the100 revolutions. Then the tablets were removed and de dusted by using a soft muslin cloth and reweighed. The weight lost should not exceed the limit 1.0%. The percentage friability was measured by using the following formula.

%Friability? (Initial Weight- Final weight / Initial Weight) X 100

Fourier Transform Infrared Spectroscopy (FTIR)

FTIR analysis was performed to evaluate drug-polymer compatibility. Samples of pure drug, polymers, and physical mixtures were scanned using an FTIR spectrophotometer across the range of 4000–400 cm?¹.

In-Vitro Drug Release Study

Dissolution studies were conducted using a USP Type II (paddle) apparatus at 50 rpm and 37 ± 0.5°C in 900 mL of pH 6.8 phosphate buffer. Samples (5 mL) were withdrawn at predetermined time intervals for up to 12 hours, filtered, and analyzed spectrophotometrically at λmax of 275 nm. The withdrawn volume was replaced with fresh buffer to maintain sink conditions.

In-vitro drug release studies details:

Apparatus used: USP XXIII dissolution test apparatus

Dissolution medium: 6.8 pH phosphate buffer solution.

Drug Release Kinetics Modeling

To understand the drug release mechanism, dissolution data were fitted to various kinetic models:

• Zero-order kinetics (cumulative % drug released vs. time),
• First-order kinetics (log % drug remaining vs. time),
• Higuchi model (cumulative % drug released vs. square root of time),
• Korsmeyer–Peppas model (log cumulative % drug released vs. log time),
• Hixson–Crowell model (cube root of % drug remaining vs. time).

The correlation coefficient (R²) was used to determine the best-fitting model. The release exponent (n) from the Peppas model was analyzed to identify the mechanism of drug release (Fickian diffusion, non-Fickian, or case-II transport).

• Optimization of Formulation

Multiple formulations were developed using different concentrations of the hydrophilic polymers. Based on drug release profile, lag time, and mechanical strength, formulation HHP-4 (with HPMC K4M) was selected as the optimized pulsatile system.

RESULTS AND DISCUSSION:

Evaluation of Hydralazine HCL

Standard calibration   Curve   of   Hydralazine HCL in methanol

• Solvent  Methanol
• Wavelength…      260 nm
• Unit for Concentration     µg/ml

Table 2: Standard Calibration data of Hydralazine HCL in methanol

Fig 2: Standard Calibration Curve of Hydralazine HCL in Methanol (λmax 260 nm)

Table-3: Standard calibration data of Hydralazine HCL in pH 6.8 buffer

Image showing prepared Pulsatile tablets using different hydrophilic polymers

Evaluation of Hydralazine HCL powder:

*Average of three replicates

Evaluation of core tablet

*Average of three replicates

Evaluation of Core-in-cup materials.

Pre-Compression Studies

The powder blends used for core tablet preparation were evaluated for flow properties. The angle of repose ranged from 24.28° to 28.56°, indicating good to excellent flow characteristics. Carr’s index values ranged from 8.32% to 17.53%, suggesting acceptable compressibility. These properties ensured uniform die filling during compression, contributing to consistent tablet weight and content.

The core tablets exhibited acceptable thickness (3.6–3.7 mm), hardness (3.4–3.8 kg/cm²), and friability (<1%). The prepared core-in-cup tablets also showed consistent physical properties: thickness ranged from 3.32 mm to 5.83 mm, and hardness from 4.50 to 8.50 kg/cm², indicating sufficient mechanical strength to withstand handling. Drug content uniformity across all formulations was within 97.23% to 99.01%, adhering to pharmacopeial specifications.

Dissolution studies conducted in pH 6.8 phosphate buffer over 12 hours showed that the core-in-cup tablets exhibited a lag phase followed by a pulsatile release of Hydralazine HCl. The drug release profile varied based on the polymer used in the top layer:

• Sodium Alginate: 97.19%–98.04%
• HPMC K4M: 96.92%–97.96%
• Sodium CMC: 96.37%–97.70%

The observed lag time and burst release behavior validated the functionality of the core-in-cup design. Among the polymers, HPMC K4M demonstrated the most effective control over lag time and sustained release, making it superior in pulsatile delivery performance.

All values are represented as mean ± standard deviation (n=3)

Table-9: In-vitro release profile of HSA2 containing 60mg Sodium alginate

All values are represented as mean ± standard deviation (n=3)

All values are represented as mean ± standard deviation (n=3)

All values are represented as mean ± standard deviation (n=3)

All values are represented as mean ± standard deviation (n=3)

All values are represented as mean ± standard deviation (n=3)

All values are represented as mean ± standard deviation (n=3)

All values are represented as mean ± standard deviation (n=3)

All values are represented as mean ± standard deviation (n=3)

All values are represented as mean ± standard deviation (n=3)